Genetic Atrioventricular Block and Progressive Cardiac Conduction Disease

Inherited conduction system disease (isolated or progressive, Lenègre–Lev disease), forms associated with cardiomyopathy, congenital heart disease and neuromuscular disease, and congenital atrioventricular block, with maternal autoimmune block as the principal differential diagnosis.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Coexistence of fainting and extreme bradycardia was described by Morgagni in the eighteenth century and later by Stokes and Adams, whose names became associated with episodes of loss of consciousness through asystole; electrocardiographic recording of atrioventricular block came later, and the first familial cardiac conduction disease description is attributed to Morquio in 1901, in a familial childhood disease with persistent pulse abnormalities and syncopal and epileptiform episodes [4]. In 1962, Combrink and colleagues described large South African families with autosomal dominant familial bundle branch block, followed by Steenkamp's families with trifascicular block and sudden death and a large Lebanese family with a similar phenotype; these lineages led decades later to identification of TRPM4 [4].

In 1964, Jean Lenègre and Maurice Lev published in Progress in Cardiovascular Diseases the pathological studies giving the condition its name: destruction of the bundle of His and conduction system branches was the principal finding in patients with complete atrioventricular block [3, 19, 20]. “Lenègre–Lev disease” came to designate the degenerative form, considered a primary degenerative disease or exaggerated ageing, with sclerosis predominantly affecting conduction tissue; the 2013 consensus of the Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA) and Asia Pacific Heart Rhythm Society (APHRS) adds that, at any age, these patients' conduction abnormalities are more marked than expected from age alone [2]. Familial transmission and progression from first-degree to complete block were documented in subsequent decades, including by Lynch and colleagues in 1973, and progressive conduction disease became recognised among primary electrical heart diseases alongside long QT and Brugada syndromes [3].

The molecular era began in 1999, when Schott and colleagues linked a large French family with autosomal dominant conduction disease to locus 3p21 and a splice variant in SCN5A, the cardiac sodium channel gene already known in long QT syndrome type 3 and Brugada syndrome [4, 21]. In 2009, Kruse and colleagues identified the TRPM4 variant responsible for progressive familial heart block type I in the South African family of Afrikaner ancestry, whose chromosome 19q13.3 linkage had been established in 1995 [4, 22]. In parallel, identification of NKX2-5 variants in 1998 in families with atrial septal defect and atrioventricular block, and LMNA in dilated cardiomyopathy with conduction disease in 1999, showed that inherited conduction disease may be isolated or part of cardiomyopathies and cardiac malformations [23, 24].

The definition of cardiac conduction disease (CCD) varies. Tadros and Cadrin-Tourigny's chapter in Clinical Cardiogenetics defines it as any persistent defect in impulse formation or propagation at any level of the specialised system without a known medicine or metabolic disturbance affecting conduction [4]. Unlike most inherited cardiovascular diseases, CCD predominantly has non-genetic causes: structural disease (ischaemic or cardiomyopathy), cardiac interventions, autoimmune processes such as neonatal lupus and, in older people, senile conduction system degeneration [4]. Primary CCD in a young patient, particularly one with a family history, should raise suspicion of an inherited cause; the mechanism may be functional (reduced depolarising currents or cell coupling) or degenerative, through premature conduction system degeneration [4]. The 2026 Japanese review by Sumitomo, Makita and colleagues proposes broadening the classical progressive conduction disease concept, restricted to a structurally normal heart, to include forms associated with cardiomyopathies, congenital heart disease, metabolic and mitochondrial diseases, with classification by genetic groups and an as-yet unvalidated diagnostic score [3].

This article covers genetic atrioventricular block (isolated/progressive), with the genes SCN5A, TRPM4 and LMNA and autosomal dominant inheritance at its core, and includes the syndromic forms and those associated with heart disease insofar as they present as conduction disease. Brugada syndrome, long QT syndrome and familial dilated cardiomyopathy, including cardiac laminopathy, are part of the differential diagnosis, without development of their specific management. Congenital atrioventricular block mediated by maternal antibodies is not a genetic disease, but it is covered in some detail because it is the cause of the vast majority of blocks diagnosed in the fetus and infant and because its recurrence among siblings may mimic a hereditary disease [4, 12].

2. Molecular Genetics and Pathophysiology

2.1. Physiological basis and disease mechanisms

Rapid impulse conduction in the His–Purkinje system depends on availability of the fast sodium current carried by Nav1.5, encoded by SCN5A, generating action potential phase 0, and high-conductance gap junction channels such as connexin 40, encoded by GJA5 [4, 9]. The atrioventricular node depends on transcription factors such as NKX2-5 for maturation and lifelong maintenance, and TBX5 controls SCN5A expression in the postnatal conduction system [4, 9]. Inherited conduction disease thus results from distinct mechanisms converging on the same electrocardiographic phenotype: sodium current loss (SCN5A), membrane depolarisation reducing Nav1.5 availability (TRPM4, KCNK17), reduced intercellular coupling (GJA5, GJC1), altered conduction system development and maintenance (NKX2-5, TBX5), fibrofatty replacement of conduction tissue in cardiomyopathy (LMNA, DES, EMD), infiltration by storage material (PRKAG2, LAMP2, GLA) and mitochondrial energy deficiency [2, 3].

The interaction with ageing is central. In the French family studied by Probst and colleagues, with the SCN5A splice variant IVS22+2T>C (historical numbering, = NM_000335.5:c.3960+2T>C, ClinVar VCV000009378; skipping of exon 22 and complete loss of function of the affected allele), 25 of 65 potentially affected members were carriers; P-wave duration, PR interval and QRS increased with age in carriers and non-carriers, but were always greater in carriers, and QRS widening became more marked after 40 years of age [25]. The authors concluded that SCN5A-related hereditary Lenègre disease results from haploinsufficiency which, combined with ageing, progressively alters conduction velocity [25]. The 2013 consensus adds that subtle structural changes, mainly fibrosis, exist in carriers of SCN5A variants [2].

2.2. Genetic architecture

The genetic architecture of inherited conduction disease is summarised in Table 2.1, combining the Clinical Cardiogenetics clinical classification, detection frequencies from the 2022 genetic testing consensus and the grading proposed in 2026 [3, 4, 10].

Table 2.1. Genetic architecture of inherited cardiac conduction disease.

AD, autosomal dominant; AR, autosomal recessive; XR, X-linked recessive; ++, frequent; +, present; ±, occasional; ?, unknown. Detection frequencies according to the 2022 consensus: >10% major gene, 1–10% minor gene [4, 10].

The 2022 EHRA, HRS, APHRS and Latin American Heart Rhythm Society (LAHRS) consensus distinguishes isolated-disease genes (SCN5A, detection frequency above 10%, and TRPM4, between 1% and 10%) from syndromic genes, among which only LMNA exceeds 10%; DES, DMD, DMPK, EMD, LAMP2, ZNF9 (CNBP), GLA, PRKAG2, TNNI3K, NKX2-5, GJC1, TBX5, MYL4 and mitochondrial DNA are rare genes or have unknown frequencies, and none has yet received ClinGen curation for conduction disease [10]. The 2026 review classifies genes into three grades — core genes, established but less frequent genes and emerging or research genes — and proposes systematic testing of grade 1 genes [3].

2.3. SCN5A: loss of function, overlap and modifiers

In Schott's original French family, the disease manifested as first-degree AVB, left bundle branch block (LBBB), RBBB or complete AVB requiring a pacemaker, without structural disease, and follow-up showed progression; in an independent Dutch family, with asymptomatic first-degree AVB, RBBB and non-specific intraventricular conduction delay, a frameshift variant was identified that cosegregated with the phenotype [4, 21]. In 2001, Tan and colleagues functionally characterised the variant NM_000335.5:c.1540G>T p.(Gly514Cys) in a family with an isolated, sustained conduction defect, with abnormalities of voltage dependence that selectively slowed conduction without causing the tachyarrhythmias associated with other SCN5A variants [26].

As in Brugada syndrome, CCD-causing SCN5A variants reduce Nav1.5 function; consequently, the same variant often produces a mixed Brugada–CCD phenotype in one patient or relatives [4]. In long QT syndrome type 3, by contrast, variants cause gain of function, with impaired inactivation and increased late sodium current; some variants reduce peak current and increase late current, with the Dutch 1795insD variant the best characterised overlap syndrome example [4]. In current nomenclature, 1795insD corresponds to NM_000335.5:c.5382_5384dup, p.(Tyr1794_Glu1795insAsp), recorded in ClinVar as pathogenic (VCV000009382); historical numbering derives from the 2016-amino-acid isoform [27]. SCN5A variants have also been described in families with sinus node dysfunction (including a recessive congenital form), atrial fibrillation and dilated cardiomyopathy, and common SCN5A-SCN10A locus variants associate with PR and QRS duration in genome-wide association studies [4, 28].

The Brugada syndrome GeneReview lists among the SCN5A allelic disorders progressive cardiac conduction system disease (Lenègre disease, isolated conduction disease) and sick sinus syndrome, and describes the common variant NM_000335.5:c.1673A>G p.(His558Arg) as a modifier, able to partially restore sodium current and to modulate the effect of variants such as NM_000335.5:c.1535C>T p.(Thr512Ile), associated with conduction disturbances [28]. The typical electrocardiographic course is a prolonged PR, broad QRS and left axis deviation, with possible progression to high-grade AVB [4].

2.4. TRPM4: a Purkinje system cation channel

TRPM4 encodes a calcium-activated non-selective cation channel, expressed mainly in Purkinje fibres [4]. In the South African family, the variant c.19G>A, p.(Glu7Lys) attenuated deSUMOylation of the channel; the resulting constitutive SUMOylation reduced endocytosis and increased channel density at the cell surface, a gain-of-function mechanism [22]. Liu and colleagues identified, in one Lebanese and two French families, the variants NM_017636.4:c.490C>T p.(Arg164Trp), c.1294G>A p.(Ala432Thr) and c.2531G>A p.(Gly844Asp), with conflicting classifications in ClinVar, all with increased current density through reduced endocytosis and dysregulated SUMOylation, and showed by immunohistochemistry that the TRPM4 signal is greater in Purkinje fibres than in ordinary ventricular cardiomyocytes [29]. The mechanistic hypothesis is that the increased density of cation channels depolarises the membrane and reduces the availability of Nav1.5 required for rapid conduction [4].

The classical phenotype is RBBB with or without fascicular block progressing to complete AVB, with isolated LBBB rare [4]. In a series of 160 probands with inherited arrhythmic syndromes, TRPM4 variants were found in eight with AVB or RBBB and none with sinus node dysfunction, Brugada syndrome or long QT [30]. In targeted sequencing of 95 PCCD patients, Daumy and colleagues identified 13 rare variants; p.(Ile376Thr), in a four-generation French family, was present in 10 of 11 tested affected individuals and 1 of 21 unaffected individuals, with increased current density and membrane expression [31]. Estimated TRPM4 testing yield in PCCD from small cohorts without systematic cosegregation is approximately 15% [4]. Loss-of-function variants (through folding and trafficking defects) have been described in children with congenital or infantile AVB, so both functional directions have been associated with conduction disease [32]. In 2025, ClinGen classified the TRPM4–Brugada syndrome relationship as refuted, and activation-gate variants in the same gene cause progressive erythrokeratodermia without a reported cardiac phenotype in those families [9].

2.5. LMNA and other cardiomyopathies with conduction disease

LMNA encodes lamins A and C, intermediate filaments of the nuclear lamina; the mechanism of the cardiomyopathy remains incompletely understood, with hypotheses of nuclear envelope fragility under repeated contraction and of disturbed gene regulation by the chromatin–lamina complex [17]. LMNA cardiomyopathy arises through loss of function associated with insertion/deletion, splice or missense variants, truncating and non-truncating, and the relationship between LMNA and dilated cardiomyopathy has been classified as definitive by ClinGen [17]. In laminopathy, the atrioventricular node and the specialised conduction system are progressively replaced by fibrofatty tissue [2]. Preclinical data from 2026, in a knock-in mouse model of the nonsense variant NM_170707.4:c.673C>T p.(Arg225Ter), showed age-dependent progressive AVB preceding cardiomyopathy, downregulation of the calcium-activated potassium channel SK3 in the atrioventricular node and attenuation of the block with pharmacological activation of that channel; this is animal research, without clinical translation [33].

LMNA variants cause a broad spectrum of laminopathies, including Hutchinson-Gilford progeria, recessive Charcot-Marie-Tooth disease type 2B1, autosomal dominant and recessive Emery-Dreifuss muscular dystrophy, limb-girdle dystrophy type 1B, Dunnigan-type familial partial lipodystrophy and Slovenian-type heart-hand syndrome, with dilated cardiomyopathy, conduction disease and brachydactyly [4, 17]. Desmin (DES) causes myofibrillar myopathy with isolated cardiac involvement in 25% of cases, isolated neurological involvement in 25% and combined involvement in 50% [4]. In an individual-patient-data meta-analysis of 230 carriers of pathogenic DES variants, conduction disease was the most frequent adverse cardiac event (41.7%), ahead of heart failure events (18.7%) and sustained ventricular arrhythmias (15.7%) [9]. The Clinical Cardiogenetics chapter on restrictive cardiomyopathy links the intermediate filament genes to AVB: Arbustini and colleagues described nine patients from four families with DES variants and a restrictive phenotype, eight of whom had AVB, below-normal left ventricular ejection fraction (40–50%) and normal ventricular dimensions (left ventricular end-diastolic diameter 40–56 mm); three of the four variants had dominant transmission (one de novo) and one was recessive, with three unaffected heterozygotes, including the parents [34]. Paller and colleagues described a patient with an LMNA frameshift variant, atrioventricular conduction defect, progressive skeletal muscle weakness and a mildly depressed ejection fraction with restrictive features; the mother and sister, both carriers, had bradycardia and conduction defects without restrictive or dilated cardiomyopathy [34]. The chapter authors hypothesise that restrictive cardiomyopathy due to variants in these genes depends on the presence of atrioventricular conduction disturbances, which remains to be demonstrated [34].

2.6. Transcription factors: NKX2-5 and TBX5

In 1998, Schott and colleagues identified one missense and two nonsense variants in NKX2-5 in four families with autosomal dominant congenital heart disease, mainly ostium secundum atrial septal defect (27 of 33 cases); all affected individuals had AVB of varying degrees, electrophysiological study in three patients localised the delay to the atrioventricular node, and follow-up showed progression [4, 23]. NKX2-5 is required for septation and for normal function of the atrioventricular node in postnatal life; in one series, AVB developed after birth and was the primary cardiac manifestation in almost a quarter of affected individuals, some without a structural defect [9, 35]. In Nkx2-5+/− mice, the atrioventricular node is hypoplastic, the AH interval lengthens with growth and the HV interval remains normal [3]. GeneGuidance also records the association with congenital non-goitrous hypothyroidism type 5, usually mild [9]. NKX2-5-related heart disease is part of the differential diagnosis.

Autosomal dominant Holt–Oram syndrome combines radial ray abnormalities, congenital heart disease (particularly atrial and ventricular septal defects) and conduction disease, and more than 70% of patients meeting strict clinical criteria have a pathogenic TBX5 variant [4, 36]. Tbx5+/− mice show reduced Cx40 and Nav1.5 expression, loss of rapid conduction in the atrioventricular bundle and branches, and prolonged PR, His, HV and QRS intervals [3]. Common TBX5 locus variants associate with PR and QRS duration in genome-wide association studies [4].

2.7. Other genes

Loss-of-function variants in HCN4, which encodes the main pacemaker channel, cause autosomal dominant sinus node dysfunction, sometimes with paroxysmal atrial fibrillation, and families with sinus bradycardia and left ventricular noncompaction, sometimes with dilatation of the ascending aorta [4]. The evidence for SCN1B (sodium channel β1 subunit) rests on three small families and is considered insufficient to establish the association with CCD [4]. In a 6-year-old boy with LBBB and second-degree AVB, who died suddenly, Makita and colleagues identified the germline variant NM_181703.4:c.173A>T p.(Gln58Leu) in GJA5 (connexin 40), also present in the mother, who had LBBB and died suddenly; in a screen of 156 probands with progressive familial heart block, it was the only connexin variant, alongside 12 sodium channel variants, and it markedly reduced junctional conductance [4, 37]. Missense variants in TNNI3K have been identified in families with supraventricular tachyarrhythmia, CCD and, sometimes, dilated cardiomyopathy [4, 9]. PRKAG2 causes a cardiac glycogen storage disease with ventricular pre-excitation, progressive conduction disease and left ventricular hypertrophy, and should be sequenced when CCD is associated with pre-excitation or unexplained hypertrophy [4, 9]. The 2026 review also includes gain of function of the TASK-4 channel (KCNK17), described in severe conduction disease with idiopathic ventricular fibrillation, and a GJC1 (connexin 45) variant in progressive atrial conduction defects with craniofacial and dentodigital bone malformations [3, 38, 39].

2.8. Common variants, polygenicity and penetrance

The contribution of common variants was quantified in UK Biobank in an analysis of 469,511 participants with exome data: among 25 carriers of pathogenic or likely pathogenic (P/LP) PCCD-associated variants in five genes, conduction disease prevalence was 28% versus 5.3% in non-carriers, with increased lifetime risk (hazard ratio [HR] 6.60; 95% confidence interval [CI] 3.14–13.8), predominantly through high-grade AVB (HR 23.2) and pacemaker implantation (HR 13.4) [40]. The 3174 carriers of uncertain variants had no increased risk, all diagnoses occurred after age 50, and PR and QRS polygenic scores added independent predictive capacity [40]. LMNA p.(Glu317Lys) explained most penetrant disease (4 of 6 carriers with AVB and pacemaker), whereas carriers of the tested TRPM4 variants had no conduction disease diagnosis [40]. These data confirm incomplete penetrance and variable expressivity in an unselected population; they cannot be transferred to phenotype-selected families.

2.9. Nomenclature of cited variants

Table 2.2. HGVS nomenclature of the variants cited in the article.

Descriptions were normalised using VariantValidator (version 4.0.1, database vvdb_2025_3, GRCh38), which confirmed each stated protein consequence [11, 27]. SCN5A c.2582_2583del, described in Clinical Cardiogenetics as recurrent in the Netherlands, lies before codon 1077 and therefore has the same numbering in the 2015- and 2016-amino-acid isoforms [4, 11].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history of primary conduction disease

Primary CCD is progressive, with a variable age at onset and clinical course. Initially, patients are usually asymptomatic and abnormalities are incidental or detected through family screening; progression produces symptoms from severe bradycardia or chronotropic incompetence, meaning inability to increase heart rate during exercise [4]. In severe bradycardia, presyncope or syncope occurs during ventricular asystole, typically exceeding 4 seconds, through sinus pauses or high-grade AVB; exercise intolerance and dyspnoea predominate in chronotropic incompetence [4]. Symptoms rarely occur without severe bradycardia, either through haemodynamic consequences of electrical dyssynchrony (excessive PR prolongation with atrioventricular dyssynchrony) or re-entry arrhythmia facilitated by very slow conduction, such as bundle branch re-entrant ventricular tachycardia [4]. The 2026 review describes combined PR and QRS prolongation over years and axis deviation as characteristic; block is typically type II (non-Wenckebach), paroxysmal or complete, with prolonged HV, and a Brugada pattern may coexist in SCN5A carriers [3]. Ventricular arrhythmias can occur independently of bradycardia [3].

Systematic longitudinal data on inherited CCD remain limited; the well-studied prognosis of conduction abnormalities in the general population without structural heart disease provides a reference but cannot be extrapolated directly because inherited mechanisms include accelerated degeneration. Those data — sinus bradycardia, first-degree AVB, Mobitz I and II second-degree AVB, RBBB and LBBB — are summarised in section 11.1 [4].

3.2. Differences between genes

In SCN5A-related forms, the first manifestation may be ventricular arrhythmia in Brugada syndrome, and syncope should also be investigated as possible tachyarrhythmia [4]. In a multicentre study published in 2025 involving 615 P/LP loss-of-function SCN5A variant carriers (with CCD or Brugada syndrome), the arrhythmic event rate was 0.7% annually, higher in symptomatic individuals, and initial symptoms, male sex and QRS prolongation were independent predictors; study figures and limitations appear in section 11.2 [41].

In TRPM4-related forms, the predominant phenotype is His–Purkinje system block, with RBBB and fascicular blocks progressing to complete AVB; onset and severity vary within families and penetrance is incomplete [4, 9]. In an Italian series of 16 TRPM4 variant carriers presented as a conference abstract in 2026, 10 had conduction disease, of whom 70% required a pacemaker before age 50, and six had Brugada syndrome; the data have not yet been published as a full paper [42].

LMNA cardiomyopathy usually presents in early or mid-adulthood with symptomatic CCD or arrhythmias, or symptomatic dilated cardiomyopathy including heart failure or mural thrombus embolism; sudden death may be the first manifestation even with minimally reduced or preserved systolic function [17]. Conduction involvement typically begins in the sinus and atrioventricular nodes — sinus bradycardia, sinus arrest with junctional rhythm, first-degree AVB progressing to second and third degree — with low-voltage P waves and initially normal QRS, accompanied by atrial arrhythmias (flutter, fibrillation, supraventricular tachycardia, tachycardia–bradycardia syndrome) and ventricular arrhythmias [4, 17]. Among 64 carriers from 16 families, 79% had electrocardiographic abnormalities (mean onset age 41.2 years) and ventricular dysfunction appeared on average at 47.6 years; ECG abnormalities preceded cardiomyopathy by a median 7 years [43]. Among 122 carriers followed for a median 7 years at five referral centres, AVB prevalence increased from 46% to 57%, atrial arrhythmias from 39% to 63%, ventricular arrhythmias from 16% to 34% and left ventricular dysfunction from 44% to 57%; 19% progressed to end-stage heart failure and 13% died [44]. Penetrance is age-dependent, with onset in the third and fourth decades, and considered above 90–95% by the seventh decade [17].

In the NKX2-5 forms, in a review of 202 patients with 59 variants, 74% had atrial septal defect with conduction disturbance, and 19 of 120 patients (15%) with familial atrial septal defect and conduction disturbance died suddenly [9, 45]. In Iceland, the NKX2-5 variant NM_004387.4 p.(Phe145Leu) (published designation, without a nucleotide change in the abstract; three distinct substitutions encode this change) was associated with dilated cardiomyopathy, heart failure, sudden death, high-grade AVB and atrial septal defect [9, 46]. In Holt-Oram syndrome, patients with or without structural heart disease are at risk of conduction disease; they may present at birth with sinus bradycardia and first-degree AVB, and AVB may progress unpredictably to complete block, with or without atrial fibrillation [36]. Conduction disturbances may worsen over time, sometimes require a pacemaker, and there are reports of sudden death due to heart block [47]. The exact prevalence of CCD in Holt-Oram syndrome has not been reported [4].

3.3. Forms associated with neuromuscular and mitochondrial disease

In Duchenne and Becker muscular dystrophies, dilated cardiomyopathy predominates and CCD is infrequent; in myotonic dystrophies due to DMPK (type 1, Steinert disease) or CNBP (type 2) expansions, CCD is very frequent and progressive and dilated cardiomyopathy rare [4]. In myotonic dystrophy type 1, most patients develop CCD; severe CCD (non-sinus rhythm, PR >240 ms, QRS >120 ms or second- or third-degree AVB) is associated with increased sudden death risk, CTG repeat number and muscle severity predict severe CCD, and sudden death accounts for 30% of mortality [4]. The Oxford Desk Reference recommends cardiology referral when PR exceeds 200 ms, QRS exceeds 120 ms, atrial fibrillation or flutter appears or symptoms occur, and records long PR, wide QRS, left axis deviation and bundle branch block as indicators of early conduction system involvement [48]. In a Japanese cohort of 506 myotonic dystrophy type 1 patients, 3.6% died suddenly; QRS ≥120 ms and prolonged PQ occurred in 20.3% and 11.8%, without significant sudden death association, whereas sudden death was associated with pacemaker presence (HR 4.35; 95% CI 1.22–15.50) [3].

In X-linked Emery–Dreifuss dystrophy (EMD), cardiac manifestations usually appear in adolescence or after age 20, with sinus bradycardia, PR prolongation and complete block; atrial standstill is almost pathognomonic, and a dilated right atrium with absent P waves should prompt exclusion of the disease [49]. Cardiac severity does not correlate with muscle involvement, and female carriers may manifest cardiac disease, particularly atrial standstill, later in life [49, 50]. GeneReviews states that EMD or FHL1 heterozygotes are usually asymptomatic but at risk of cardiac disease, generally after age 50 [50]. In the Clinical Cardiogenetics summary table, rhythm and conduction disturbances affect more than 95% by age 30 in both X-linked and autosomal dominant forms (LMNA, DES and other myofibrillar myopathies), and dilated cardiomyopathy affects 35% in the autosomal dominant form, with sudden death despite pacing [49]. In Kearns–Sayre syndrome, caused by mitochondrial DNA deletions, atrioventricular block progresses rapidly; the Brazilian book Síndromes Genéticas: Reconhecer para Tratar includes conduction block among major criteria, notes that ophthalmoplegia usually precedes conduction defects and attributes 20% of deaths to heart block [4, 51].

3.4. Childhood conduction disease

In the French national cohort of 385 children with isolated non-immune AVB diagnosed from fetal life to age 18 (1980–2022, 29 centres), median diagnosis age was 3 years; 81.6% were asymptomatic, 68.3% had complete AVB at diagnosis and 84 of 122 (68.8%) with incomplete block progressed to complete AVB over a median 12 years [12]. Of 204 parents with ECGs, 38.2% had conduction abnormalities, including long PR (14.2%), complete or incomplete RBBB (30.9%) and one unrecognised complete AVB in a 56-year-old father [12]. These observations, together with heritability estimated in earlier studies by the same group, support the hypothesis that childhood non-immune AVB is partly an inherited progressive disease [12].

4. Clinical Recognition and Warning Signs

Recognition of inherited disease depends predominantly on age, family history and associated manifestations because CCD is common in older people and almost always degenerative or secondary [4]. In a prospective study of 855 men born in 1913, bundle branch block prevalence increased from 1% at age 50 to 17% at age 80; US and Australian studies estimate pacemaker prevalence below 0.5% before age 65 and above 2% after age 75 [4]. In the Japanese hospital series in the 2026 review, only 65 of 1289 AVB implants (5%) occurred before age 50 [3]. Table 4.1 brings together warning signs and their interpretation.

Table 4.1. Warning signs of inherited conduction disease.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

A clinical diagnosis of CCD requires a conduction abnormality on ECG at one or more levels after exclusion of secondary causes [4]. The 2013 HRS/EHRA/APHRS consensus defines PCCD as unexplained progressive conduction abnormalities in individuals younger than 50, with a structurally normal heart and no skeletal myopathy, particularly with a family history; index-case diagnosis rests on clinical history, family history and 12-lead ECG, with imaging to exclude congenital heart disease or cardiomyopathy [2]. The 2021 European Society of Cardiology (ESC) guidelines reiterate this definition [5]. The 2026 review proposed an exploratory score — Mobitz II, paroxysmal or complete AVB (2 points), QRS increase ≥20 ms (2) or QRS >120 ms (1), HV >55 ms, syncope with bradycardia, onset before age 50 and family history — with high probability from 3.5 points; the authors emphasise it is unvalidated and requires prior exclusion of long QT, short QT and Brugada syndromes, maternal antibody block and acquired causes [3].

5.2. Additional investigations

Echocardiography is indicated in every case to assess causal or associated structural disease [4]. ESC recommends cardiac imaging in suspected or documented symptomatic bradycardia (class I, level C) and considers multimodality imaging — cardiac magnetic resonance (CMR), computed tomography or positron emission tomography (PET) — for tissue characterisation when conduction disturbance requires a pacemaker, particularly before age 60 (IIa, C) [5]. Cardiac sarcoidosis and giant cell myocarditis are frequent causes of unexplained high-grade AVB in young patients (younger than 55–60) [4]. In a Finnish registry, 143 of 325 cardiac sarcoidosis patients (44%) had unexplained Mobitz II or third-degree AVB [5]. The 2022 consensus states that cardiac sarcoidosis should be systematically excluded before considering a genetic diagnosis in sporadic isolated AVB, using CMR or fluorodeoxyglucose PET, and that late gadolinium enhancement CMR may be considered, particularly in LMNA variant carriers [10]. In endemic regions, Lyme serology should be performed in young patients with unexplained AVB because block is usually reversible with antibiotics [4, 15].

Assessment includes serial ECG; Holter and event or implantable recorders in symptomatic patients without ECG pacemaker criteria to detect intermittent deterioration; exercise testing for exercise intolerance to detect chronotropic incompetence or exercise-induced AVB; and electrophysiological study in selected cases [4, 10]. In patients with bundle branch block and unexplained syncope, ESC indicates a pacemaker when baseline HV is ≥70 ms, intra- or infra-Hisian block develops with incremental atrial pacing or pharmacological challenge is abnormal (class I, B); in Scheinman's study cited by the guideline, progression to AVB at 4 years was 4% with HV <70 ms, 12% with HV 70–100 ms and 24% with HV >100 ms [5]. In suspected laminopathy, GeneReviews adds assessment of muscle weakness and creatine kinase measurement [17].

5.3. Genetic testing: indications and strategy

Indications differ slightly between documents, as summarised in Table 5.1.

Table 5.1. Genetic testing indications in conduction disease by document.

Sources: [2, 5, 10, 13, 15].

Clinical Cardiogenetics proposes a phenotype-driven strategy: in isolated CCD, sequencing of TRPM4 and SCN5A; with associated dilated cardiomyopathy, LMNA, DES and SCN5A; with congenital heart disease such as atrial septal defect, NKX2-5 and TBX5; with pre-excitation or hypertrophy, PRKAG2 [4]. GeneReviews advises against single-gene LMNA testing when laminopathy is suspected and recommends a multigene cardiomyopathy panel, or a combined cardiomyopathy and arrhythmia panel when arrhythmia predominates with minimal cardiomyopathy, or genome sequencing [17]. If LMNA sequencing is negative in a typical picture (CCD, dilated cardiomyopathy, arrhythmia and family history), deletions should be sought, for example by multiplex ligation-dependent probe amplification (MLPA), and the same applies to TBX5 in typical Holt-Oram syndrome without a point variant [4]. In families with inherited disease without an identified variant, extended panels, exome or targeted deletion testing with cosegregation analysis may be considered, recognising that the yield is probably low [4].

Yield estimates depend on population and era. In the Netherlands, CCD yield, predominantly through SCN5A sequencing, was approximately 30%, with recurrent c.2582_2583del accounting for most cases [4]. The 2022 consensus cites panel or exome studies detecting variants in more than 50% of index cases, with SCN5A and LMNA approximately 20% each and TRPM4 5–10%, whereas the 2018 American guideline, citing the 2011 consensus, attributes only 5% of progressive conduction disease to SCN5A [10, 15]. In an Italian series of 39 patients with unexplained CCD before age 50, 38% had variants (3 pathogenic, 6 likely pathogenic and 4 uncertain), predominantly in SCN5A, TRPM4 and LMNA, and results led to ICD implantation in two patients [53]. In the French paediatric cohort, only 7 of 133 tested children (5.3%) had a P/LP variant; the French authors attribute some Italian yield to inclusion of cardiomyopathy (13%) and sinus node dysfunction (33%) [12]. Distinguishing “proportion of variant-positive cases” from clinical sensitivity is therefore important: none of these numbers excludes inherited disease following a negative test.

5.4. Test limitations and reporting

Sequencing detects single nucleotide variants and small insertions and deletions but usually not exon or whole-gene deletions or duplications, requiring targeted methods (MLPA, quantitative PCR, targeted microarray) or validated panel copy-number analysis [17]. At least three reports document LMNA deletion cardiomyopathy [17]. A variant of uncertain significance neither establishes nor excludes diagnosis [17]; UK Biobank carriers of PCCD-associated uncertain variants had no increased conduction disease risk [40]. Reports should state gene, versioned transcript (for example NM_000335.5 for SCN5A and NM_017636.4 for TRPM4), HGVS nomenclature, zygosity, ACMG/AMP classification and technical limitations; population frequencies should be assessed against disease rarity, and the UK Biobank study used a 0.01% allele frequency threshold for classification [11, 40]. TRPM4 appears in many arrhythmia panels and most missense variants identified are uncertain; ClinVar records more than 1200 uncertain submissions for the gene [9]. Partial familial segregation and response to treatment do not, by themselves, justify reclassification of a variant.

5.5. Practical algorithm

1. 12-lead ECG documenting the abnormality and probable block level; exclude reversible causes (medicines, hyperkalaemia, hypothermia, thyroid dysfunction, vagal tone) [4].
2. Echocardiography for all; CMR or PET in patients younger than 60 with unexplained high-grade AVB to exclude sarcoidosis and myocarditis; Lyme serology in endemic areas [4, 5, 10].
3. Holter, event or implantable recorder and exercise testing according to symptoms; electrophysiological study in selected settings [4, 5].
4. Three-generation pedigree, neuromuscular examination, CK and upper limb assessment [4, 17].
5. Genetic testing for onset before age 50, family history, cardiomyopathy, congenital heart disease, extracardiac disease or suspected laminopathy, with a phenotype-guided panel including SCN5A, LMNA, TRPM4, PRKAG2, GLA and relevant syndromic genes, and deletion analysis when indicated [4, 10].
6. In the fetus or infant, quantitative maternal anti-Ro/SSA and anti-La/SSB antibodies; if negative, patient genetic testing with family cascade [12, 52].

6. Differential Diagnosis

Unlike most inherited cardiovascular diseases, cardiac conduction disease predominantly has non-genetic causes, and inherited disease diagnosis is largely one of exclusion: the Clinical Cardiogenetics operational definition requires a persistent conduction defect without an explanatory medicine or metabolic disturbance, and its Table 17.1 organises aetiologies into three groups — primary (senile, inherited, idiopathic), secondary (ischaemic heart disease, cardiomyopathies, sarcoidosis and myocarditis, neonatal lupus syndrome, congenital heart disease, iatrogenic and rare causes) and transient or reversible (increased vagal tone, metabolic disorders and medicines) [4]. The 2026 Japanese review proposes a similar two-step sequence: first exclude known conduction disturbance causes, then confirm that the abnormality is neither transient nor reversible; only then apply the authors' proposed progressive conduction disease probability score, whose exclusions include long QT with functional block, short QT, Brugada syndrome (recognising overlap with some SCN5A variants), congenital AVB due to maternal anti-SS-A/SS-B antibodies, AV nodal artery ischaemia, tumours (myxoma or metastases) near the node, sarcoidosis, viral myocarditis (coxsackie, adenovirus, influenza, COVID-19) and other agents (Lyme disease, Chagas disease, diphtheria), rheumatic fever, infective endocarditis, aortic (surgical or transcatheter) and mitral valve replacement, surgical closure of an atrioventricular septal defect, congenitally corrected transposition of the great arteries, polysplenia, ablation near the AV node, Wenckebach block, vasovagal reflex, slow nodal conduction, hyperkalaemia and AV-conduction-prolonging medicines [3].

In practice, three variables guide differential reasoning: onset age, structural or systemic disease and family history. Conduction disease prevalence rises markedly with age and, within a family, disease in the young is rare and more likely inherited, whereas disease in older people is common and more likely degenerative; clinical review of affected relatives, including onset age and comorbidities, helps recognise inheritance patterns and phenocopies [4]. The 2022 EHRA/HRS/APHRS/LAHRS consensus adds that an inherited form is likely with a CCD ECG without acquired-cause evidence, but cardiac sarcoidosis is relatively common in isolated AVB and should be systematically excluded before considering a genetic diagnosis in sporadic isolated AVB [10]. The following subsections address each group, and Table 6.1 at the end summarises distinguishing features.

6.1. Primary disease: inherited, degenerative (senile) and idiopathic

Primary conduction disease, without structural heart disease or an identifiable secondary cause, has three forms in Clinical Cardiogenetics. Progressive senile disease presents with progressive sinus node dysfunction, atrial arrhythmias and/or atrioventricular conduction defects, typically fascicular blocks (wide QRS), beginning late, for example after age 50; inherited disease has the same electrocardiographic expression but premature onset (for example before age 50), a family history of CCD, sudden death, dilated cardiomyopathy or congenital heart disease and/or a pathogenic susceptibility-gene variant; idiopathic disease is unexplained CCD [4]. Inherited disease mechanisms are functional (less depolarising current or impaired intercellular coupling) or associated with premature conduction system degeneration, termed Lenègre disease [4]. The 2018 ACC/AHA/HRS guideline emphasises that degenerative causes are most commonly encountered clinically and associated with advanced age, chronic hypertension and diabetes mellitus [15].

The boundary between inherited and degenerative forms is unclear for two reasons. First, inherited onset varies: all UK Biobank conduction disease diagnoses in P/LP variant carriers occurred after age 50 (section 2.8) [40]. Second, degenerative disease is very frequent in the population and bundle branch block and pacemaker prevalence rise markedly with age (section 4) [4]. Consequently, the 2026 review warns that progressive conduction disease is probably underdiagnosed in young people, often misclassified as degenerative and highly age-dependent [3]. The 2013 consensus sets age 50 as the limit for progressive conduction disease definition, but Clinical Cardiogenetics presents cut-off ages as examples rather than absolute limits, and UK Biobank data show pathogenic variant carriers may manifest disease later [2, 4, 40].

The idiopathic category depends on investigation extent. The French cohort of 385 children with isolated non-immune AVB contrasts with a Danish study of young people receiving pacemakers for unexplained AVB, reporting a 3.8-fold higher rate of death, heart failure hospitalisation, ventricular tachyarrhythmia or aborted sudden death versus controls; the French authors attribute the difference at least partly to insufficient investigation in that cohort, where aetiology remained unknown in 50.3%, maternal immune status and genetic testing were absent in most and only 0.6% had genetic AVB [12]. “Idiopathic” CCD in a young patient should therefore remain provisional until sarcoidosis, myocarditis, neuromuscular disease and genetic forms with specific risks such as laminopathies have been excluded [10, 12].

Within the inherited forms themselves, the electrocardiographic pattern contributes to the differential diagnosis. OMIM distinguishes progressive familial heart block type I (PFHB1, OMIM 113900), a bundle branch disease with RBBB, hemiblocks and wide-QRS complete AVB progressing from normal ECG to RBBB then complete AVB, from type II (PFHB2, OMIM 140400), where complete AVB has a narrow QRS, frequently after sinus bradycardia with left posterior hemiblock; PFHB2 was described in a large four-generation South African family of Dutch ancestry linked to 1q32 without an identified gene [8]. OMIM 115080 also records Lynch and colleagues' family (1973), with multigenerational progressive AV conduction defect, conduction prolongation usually beginning in the fourth decade, loss of R waves in right precordial leads and generally slow progression from first to third degree, fulminant in some members [7]. Clinically, wide QRS with fascicular blocks suggests His–Purkinje disease (SCN5A, TRPM4), whereas narrow-QRS AVB, particularly with low-voltage P waves or congenital heart disease, suggests LMNA, NKX2-5 or TBX5 [4].

6.2. Secondary causes: structural heart disease, inflammation, infection and iatrogenic disease

Ischaemic heart disease is suggested by known coronary disease or atherosclerotic risk factors, ECG Q waves and regional wall-motion abnormalities or imaging scar, typically septal [4]. The 2018 ACC/AHA/HRS guideline notes that AVB from inferior-wall ischaemia or infarction may be reversible, and the 2026 review includes AV nodal artery ischaemia among exclusions [3, 15]. Any cardiomyopathy, most commonly dilated cardiomyopathy, may progressively affect the conduction system proportionately to myocardial involvement; CCD disproportionate to cardiomyopathy severity should suggest primary CCD such as LMNA-related disease [4].

Cardiac sarcoidosis and giant cell myocarditis are common causes of unexplained high-grade AVB in young patients (younger than 55–60), and advanced CMR or cardiac fluorodeoxyglucose PET should be considered [4, 10]. Sarcoidosis preferentially affects the basal interventricular septum, and AVB is the commonest presentation of clinically overt cardiac sarcoidosis; in the Finnish registry cited in section 5.2, 44% had unexplained Mobitz II or third-degree AVB [5]. Diagnosis rests on electrocardiographic monitoring, echocardiography, CMR and myocardial or other affected tissue biopsy, potentially aided by PET [5]. Immunosuppression reversibility is unpredictable: in small non-randomised corticosteroid studies, only 13–47% showed some AVB reversal, and initial improvement may not persist [15]. Distinction has therapeutic consequences because sarcoidosis-associated AVB carries high long-term sudden death risk even with LVEF above 35% [5].

Among infections, Lyme carditis, caused by Borrelia burgdorferi and transmitted by Ixodes ticks, most frequently manifests as AVB, usually AV nodal, and should be sought in young people with unexplained AVB in endemic areas, with serological confirmation [4, 15]. Approximately 40% of clinically identified patients require temporary pacing, but permanent AVB after antibiotics is rare; a published-case review found median resolution time 6 days, with cases up to 42 days [15]. Chagas disease in people from Trypanosoma cruzi-endemic Central and South American areas causes varying conduction defects, and advanced block is permanent [16]. The 2021 PACES paediatric consensus also lists diphtheritic myocarditis, infectious mononucleosis, bacterial endocarditis with perivalvular abscess, rheumatic fever and, more recently, transient conduction abnormalities in COVID-19-associated multisystem inflammatory syndrome in children; in acute myocarditis with complete AVB, conduction recovered in 67% of young patients within 7 days [16].

Congenital heart defects most associated with CCD are congenitally corrected transposition of the great arteries, potentially first presenting as adult CCD, and partial or complete atrioventricular septal defect, frequent in Down syndrome; diagnosis requires cardiac imaging, and CCD coexisting with congenital heart disease also occurs in NKX2-5 and TBX5 inherited forms [4]. Iatrogenic CCD results from surgical or percutaneous procedures near the conduction system, particularly aortic valve replacement, septal defect closure, arrhythmia ablation and septal reduction in hypertrophic cardiomyopathy [4]. After transcatheter aortic valve replacement, new LBBB occurs in 19–55% and high-grade AVB in approximately 10%, persisting beyond 48 hours in 2–20% [15]. Postoperative AVB complicates 3–8% of congenital heart operations and 1–3% require permanent pacemakers [16]. Rare causes include infiltrative malignancy and cardiac tumours, trauma and rheumatological disease; amyloidosis, haemochromatosis, rheumatoid arthritis, scleroderma and systemic lupus erythematosus are also listed as intrinsic causes of bradycardia and AV junction disturbance in European pacing guidance [4, 5].

6.3. Transient or reversible causes

European pacing guidance considers distinguishing reversible from irreversible bradycardia essential and lists medicine adverse effects, acute myocardial infarction, toxic exposure, infections, surgery and electrolyte disorders; in a study of 277 patients brought to emergency care with bradycardia, the cause was electrolyte disturbance in 4%, poisoning in 6%, acute infarction in 14% and medicine adverse effects in 21% [5]. It recommends targeted tests with clinical suspicion — thyroid function, Lyme serology, digoxin level, potassium, calcium and pH — and includes among extrinsic causes physical training, vagal reflexes, hypokalaemia, hyperkalaemia, hypercalcaemia, hypermagnesaemia, hypothyroidism, anorexia, hypoxia, acidosis, hypothermia, intracranial hypertension, central nervous system tumours, temporal lobe epilepsy and obstructive sleep apnoea [5].

Increased vagal tone is common in well-trained endurance athletes and may be triggered by emotion or posture in susceptible individuals; it manifests as sinus bradycardia and varying narrow-QRS AVB [4]. Mobitz I second-degree AVB without heart disease, as in athletes, usually reflects AV nodal block and has a benign prognosis, unlike infranodal Mobitz II with high risk of complete AVB progression, syncope and sudden death [4]. American guidance adds that AV nodal block progresses more slowly, has a faster, more reliable junctional escape rhythm and responds to autonomic manipulation (atropine, isoproterenol, adrenaline), whereas intra- or infra-Hisian block may progress rapidly and unexpectedly with slow, unpredictable ventricular escape; unusually, such as at night with concomitant sinus slowing, narrow-QRS high-grade block may be vagal [15]. Nocturnal bradyarrhythmias including all AVB degrees are particularly common in young people and athletes, generally physiological and vagally mediated, and when associated with obstructive sleep apnoea are effectively suppressed by apnoea treatment; nocturnal bradycardia alone does not indicate pacing [15].

Medicines altering cardiac autonomic modulation or ion channel function — beta-blockers, calcium channel blockers, sodium channel blockers, digitalis and amiodarone — are classical transient CCD causes [4]. However, several series show that therapeutic doses rarely explain new AVB alone: reversal after withdrawal is uncommon and, even with acute reversal, subsequent pacemaker implantation is frequently necessary [15]. Conversely, new AVB in patients long treated with stable AV nodal blocker doses often fails to resolve or recurs, so guidance considers continued recurrence surveillance or even permanent pacing consideration useful after withdrawal [15]. Conduction-slowing medicines should be avoided in loss-of-function SCN5A carriers and patients with overt CCD [4]. Digitalis toxicity, although increasingly infrequent, still causes AVB reversible with withdrawal or, in severe cases, digoxin antibody fragments [15].

Among metabolic causes, hyperkalaemia is the most cited reversible non-ischaemic AVB cause [15]. Severe hypothyroidism such as myxoedema is rarely associated with reversible AVB, and there is little reversibility evidence in milder thyroid abnormalities commonly encountered: in a series of 50 patients with AVB during hyper- or hypothyroidism, only approximately 20% recovered conduction after euthyroidism [15]. In sarcoidosis and hypothyroidism too, treating the cause usually does not avoid a pacemaker otherwise indicated [15]. Identifying a potentially reversible factor therefore does not exclude underlying primary CCD, and persistent AVB after correction returns the patient to section 5's algorithm [4, 15].

6.4. Autoimmune congenital atrioventricular block (cardiac neonatal lupus)

In fetuses and infants, the main differential diagnosis of inherited CCD is congenital heart block associated with maternal anti-Ro/SSA antibodies, with or without anti-La/SSB. Clinical Cardiogenetics describes transplacental antibody transfer producing non-progressive AV nodal congenital AVB with narrow QRS and warns that sibling recurrence may mimic inheritance [4]. Isolated AVB in a structurally normal heart has an estimated prevalence of 1 in 15,000–20,000 live births, and 90–95% of cases diagnosed before 6 months arise from maternal antibodies causing AV nodal inflammation and fibrosis and irreversible complete AVB [12]. The editorial accompanying the French cohort estimates more than 90% of very early-onset AVB is immune-mediated [54]. Orphanet records birth prevalence of 4.54 per 100,000 for all-cause congenital heart block (ORPHA:60041) [6].

Immune-mediated block is typically detected in the second trimester in a structurally normal fetus and is almost universally associated with anti-Ro/SSA exposure transferred through the neonatal Fc receptor [14]. Maternal IgG transfer intensifies from the end of the first trimester, coinciding with the vulnerability window at 18–24 weeks [55]. Histopathology shows extensive fibrosis potentially replacing the AV node and macrophage infiltration in fetuses dying soon after diagnosis; the current pathogenic hypothesis involves phagocytosis of immune complexes containing Ro-associated RNA, activation of Toll-like receptors 7/8 and cytokine secretion transforming fibroblasts into myofibroblasts [14]. Besides third-degree AVB, the cardiac neonatal lupus spectrum includes first- and second-degree AVB, endocardial fibroelastosis, dilated cardiomyopathy and valvular dysfunction, and neonatal lupus has non-cardiac skin, liver and haematological manifestations [55].

Block risk is estimated at approximately 2% when an anti-Ro/SSA-positive mother is primigravid or has no affected children, with recurrence six- to tenfold higher; maternal health does not influence recurrence risk [14]. The 2026 Brazilian review gives similar values: 1–2% of exposed pregnancies and recurrence of 15–20% subsequently [55]. Recurrence may approach 50% after more than one affected child [14]. Many mothers have no diagnosed autoimmune disease: in PATCH, 29.6% were asymptomatic and 22.2% had undifferentiated autoimmune syndrome, and in the São Paulo cohort several cases were identified only because the centre routinely requests maternal antibodies when diagnosing congenital block [14, 55]. Third-degree AVB has 17.5% case fatality, predominantly fetal or neonatal, and more than 70% require a pacemaker before adulthood [14]. Dilated cardiomyopathy affects 15–30% with immune-mediated block, and antibody status predicts heart failure and death more than prolonged right ventricular pacing [54].

The Oxford Desk Reference notes that maternal SLE may cause congenital heart block; its maternal-disease-related cardiac risk table assigns maternal SLE “20–40%” complete heart block without defining the denominator [56]. This does not agree with estimates of approximately 2% in anti-Ro/SSA-positive pregnancies without a previously affected child and 1–2% of exposed pregnancies adopted here [14, 55].

Several elements distinguish immune-mediated from genetic block. In the French non-immune AVB cohort, 22 fetuses were diagnosed at median gestational age 32.5 weeks, later than the typical immune-mediated window, and one was identified through family screening [12, 55]. Non-immune AVB patients are diagnosed and paced later and have better prognosis than immune-mediated patients, whose neonatal mortality and dilated cardiomyopathy risk are high [12]. Under the Clinical Cardiogenetics definition, immune-mediated block is non-progressive and nodal, whereas inherited SCN5A and TRPM4 forms tend to involve His–Purkinje tissue and progress [4]. The 2026 Japanese review expressly excludes congenital AVB in children of mothers with anti-SS-A/SS-B antibodies from progressive conduction disease [3]. Quantitative maternal antibody testing is therefore the first step in fetal or neonatal AVB; if negative, the 2025 editorial and French authors advocate considering arrhythmia and cardiomyopathy panels in all infants or children with CCD and anti-Ro/SSA-negative mothers, followed by cascade screening when positive [12, 54]. Section 10's case illustrates the qualitative-test pitfall: the pregnant woman screened qualitatively positive for anti-Ro/SSA and received dexamethasone and intravenous immunoglobulin, but late AVB onset and absent extranodal damage such as endocardial fibroelastosis prompted quantitative testing, showing negative anti-Ro52 and anti-Ro60 titres; the authors cite personal communication that approximately 30% of qualitatively positive pregnant women have negative quantitative titres, and investigation ultimately identified a multigenerational TRPM4 variant [52].

6.5. Secondary prevention of autoimmune block: hydroxychloroquine and antibody levels

Distinguishing immune-mediated from genetic block affects subsequent pregnancies because only the former has a preventive measure supported by prospective evidence. PATCH (Preventive Approach to Congenital Heart Block with Hydroxychloroquine) was a multicentre open-label, single-arm phase 2 study with Simon's optimal two-stage design, recruiting between 2011 and 2018 in the United States and one UK centre mothers with anti-Ro/SSA, with or without anti-La/SSB and regardless of maternal diagnosis, who had previously had a pregnancy complicated by second- or third-degree block or severe cardiac injury [14]. Participants received hydroxychloroquine 400 mg daily, starting before completion of gestational week 10 and continuing until delivery; the primary outcome was second- or third-degree block at any time in pregnancy or at birth [14]. Fetal echocardiography was recommended from 16–18 weeks, weekly until 26 and fortnightly until 34 according to treating physicians, and surveillance after 26 weeks was progressively reduced because de novo advanced block was rare thereafter [14].

In intention-to-treat analysis, 4 of 54 evaluable pregnancies reached the primary outcome (7.4%; 90% CI 3.4–15.9%), below the historical comparator rate of 18%; as nine mothers received dexamethasone or intravenous immunoglobulin after enrolment, nine more were recruited to assess hydroxychloroquine alone, and per-protocol analysis of 54 pregnancies exposed only to that medicine also gave 7.4% (90% CI 2.6–16.2%) [14]. Across all 63 pregnancies, there were 5 primary outcomes (7.9%), cutaneous neonatal lupus in 4 (6.4%) and delivery before 37 weeks in 9 (14.3%), prematurity not attributed to the medicine by the authors; second-trimester hydroxychloroquine levels exceeded 200 ng/mL in 60 of 61 assays, confirming adherence [14]. The historical rate derived from 257 pregnancies after an affected child in the United States, France and United Kingdom; in that study, advanced block recurred in 2 of 40 (5.0%) hydroxychloroquine-treated mothers and 43 of 217 (19.8%) untreated mothers [14].

PATCH limitations are lack of randomisation and concurrent controls, dependence on a historical comparator and potentially confounding medicines in some participants; authors considered a placebo-controlled trial infeasible, requiring at least 100 participants per arm in a rare disease, and hydroxychloroquine withdrawal in pregnant women with SLE ethically problematic [14]. For safety, literature cited suggests hydroxychloroquine is safe in pregnancy without increased congenital malformations or offspring auditory or visual abnormalities, but prolonged use carries maculopathy risk and long-term safety was not assessed [14]. PATCH and earlier data do not support dexamethasone or intravenous immunoglobulin prophylaxis: in a retrospective prophylactic fluorinated steroid study of 6 mothers, there were 2 miscarriages, 2 stillbirths and 2 liveborn infants with growth restriction and mild adrenal insufficiency, and two prospective intravenous immunoglobulin studies at 400 mg/kg did not reduce recurrence [14]. Doses, regulatory status and coordination with obstetric surveillance appear in section 8.6.

The retrospective Hospital das Clínicas, University of São Paulo Medical School cohort (2002–2022) adds Brazilian data: among 182 anti-Ro- and/or anti-La-positive pregnant women, 13 fetuses (7.1%) had third-degree AVB, all referred from 26 weeks onwards and none from mothers already followed at the institution, introducing referral bias [55]. Mothers of affected fetuses had higher median anti-Ro (240 versus 42) and anti-La levels (150 versus 10), lower C4, less than one year since diagnosis and more frequent disease activity at conception, and less frequently took hydroxychloroquine 400 mg daily before pregnancy (30.8% versus 60.5%; p = 0.044); 62% of affected newborns required pacemakers during neonatal admission [55]. Authors emphasise that antibody thresholds depend on assay method and cannot be extrapolated between platforms, and retrospective design and few cases limit conclusions [55].

6.6. Syndromic, neuromuscular, mitochondrial and storage forms

An important part of “isolated” CCD differential diagnosis is actually seeking systemic disease in which conduction is one manifestation, because associated disease may present first rather than CCD and, in LMNA, CCD typically precedes dilated cardiomyopathy [4]. Recognition changes counselling and, in several diseases, the pacing or ICD threshold (section 7) [5].

Neuromuscular diseases. The European pacing guideline distinguishes the dystrophies in which dilated cardiomyopathy predominates (Duchenne, Becker and limb-girdle forms 2C, 2F and 2I), whose patients follow the rules for non-ischaemic cardiomyopathies, from those that frequently present with conduction disease and arrhythmias (myotonic dystrophies types 1 and 2, Emery-Dreifuss and limb-girdle dystrophy type 1B) [5]. In myotonic dystrophy, myotonia, muscle pain and weakness, cataracts, gastrointestinal complaints and mild CK elevation guide the diagnosis, and confirmation is by testing for the expansions in DMPK or CNBP [4]. In Emery-Dreifuss dystrophy, the triad of early joint contractures, humeroperoneal weakness and cardiac disease is incomplete in childhood: contractures may be absent or subtle in the first decade and cardiac disease is usually absent in the first two, which makes clinical distinction from other myopathies difficult [50]. GeneReviews attributes 8.5% of cases to EMD, 1.2% to FHL1 and 26.5% to LMNA, and 63.4% remain without an identified gene; immunodetection of emerin, absent in 95% of patients with the X-linked form, may help in the presence of variants of uncertain significance [50]. The same document includes in the differential with cardiac involvement the limb-girdle dystrophies with heart disease (about 35 genes), myotonic dystrophy type 2, the desminopathies, Becker dystrophy, Danon disease (LAMP2) and BAG3 myopathy, and notes that ankylosing spondylitis, which is acquired, may combine spinal contractures and cardiac disease without evident muscle involvement [50]. Hereditary myopathies in general, the dystrophinopathies and Emery-Dreifuss dystrophy are part of the differential diagnosis [49, 50].

Mitochondrial disease. In Kearns-Sayre syndrome, caused by mitochondrial DNA deletions, the most common cardiac manifestation is conduction disease, which may progress to complete AVB and sudden death [5]. The 2026 review describes, on serial ECGs, progressive prolongation of PR, QRS and QT, with torsade de pointes in one patient, in the context of chronic progressive external ophthalmoplegia, ataxia and pigmentary retinal degeneration [3]. Ophthalmoplegia usually precedes the conduction defects [51]. Mitochondrial diseases, including Kearns-Sayre syndrome, are part of the differential diagnosis.

Neurodevelopmental disease with conduction defects. Recessive EXOSC5-related disease combines hypotonia, ataxia and cerebellar and brainstem hypoplasia with atrioventricular block, which may require a pacemaker in childhood and may manifest during anaesthesia.

Syndromic congenital heart disease. In Holt-Oram syndrome, TBX5 sequencing identifies a pathogenic variant in more than 70% of patients meeting clinical criteria, and failure of identification in up to 30% suggests non-coding or regulatory variants, or another diagnosis [36]. The differential includes Okihiro syndrome and acro-renal-ocular syndrome (SALL4; heart disease in 15%, with Duane anomaly, renal anomalies and sensorineural deafness), Fanconi anaemia (heart disease in 6%, with progressive bone marrow failure), Townes-Brocks syndrome (SALL1; heart disease in 20%, with anorectal malformation) and thrombocytopenia-absent radius syndrome; a bifid thumb has not been described in any patient with molecularly confirmed Holt-Oram [36]. Gain-of-function TBX5 variants are associated with a distinct phenotype of radial dislocation or subluxation without thumb involvement, scapular dysplasia and paroxysmal atrial fibrillation [36]. In the European EUROCAT registries (1990–2011, 34 registries), the mean prevalence of Holt-Oram diagnosed prenatally or in the first years was 0.7 per 100,000 births, with heart disease in 78.7% [57]. An atrial septal defect with AVB, especially if the AVB progresses after birth or there are relatives with atrial septal defect or sudden death, suggests NKX2-5 [4, 9].

Storage and infiltrative diseases. The 2022 consensus recommends including four genes in CCD panels — SCN5A, LMNA, GLA and PRKAG2 —, which reflects the importance of Fabry disease and PRKAG2 cardiomyopathy as phenocopies with their own treatment or risk [10]. PRKAG2 combines ventricular pre-excitation, left ventricular hypertrophy and progressive conduction disease, and Danon disease (LAMP2) and transthyretin amyloidosis are part of the differential of hypertrophic cardiomyopathy phenocopies [4, 10]. In cardiac amyloidosis, conduction defects, tachyarrhythmias and sudden death are common [5]. Fabry disease, hypertrophic cardiomyopathy and cardiac laminopathies are part of the differential diagnosis.

6.7. Overlap with other channelopathies: Brugada syndrome, long QT type 3 and functional 2:1 block

SCN5A CCD is not a watertight entity with respect to Brugada syndrome. Loss-of-function SCN5A variants can produce both phenotypes in the same patient or in the same family, and the first manifestation may be a ventricular arrhythmia in the context of Brugada [4]. The GeneReviews chapter on Brugada syndrome notes that first-degree AVB, intraventricular conduction delay, RBBB and sinus node disease are not unusual in that syndrome, and that the sodium channelopathy is associated with progressive, age-dependent prolongation of the PQ, QRS and HV intervals [28]. The 2026 review acknowledges this overlap by excluding Brugada syndrome from the progressive conduction disease score, with the caveat that some SCN5A variants cause both [3]. In practice, a patient with CCD and an SCN5A variant should also be assessed for Brugada, and syncope should be investigated as a possible tachyarrhythmia and not only as bradycardia (sections 3 and 5) [4]. Brugada syndrome is part of the differential diagnosis.

In long QT type 3, SCN5A variants generally cause gain of function, contrasting with loss of function in Brugada and progressive conduction disease, but some families associate the same variant with both phenotypes [28]. Dutch 1795insD, NM_000335.5:c.5382_5384dup, p.(Tyr1794_Glu1795insAsp), is the classical sodium channelopathy overlap syndrome example (section 2.3) [4, 27]. The French non-immune paediatric AVB cohort notes that LMNA or SCN5A variants in this overlap syndrome may be missed without genetic testing [12].

In the fetus and newborn, long QT may present with 2:1 second-degree AVB, a functional block that the 2026 review expressly excludes from the definition of progressive conduction disease [3]. In a large Japanese study of infantile long QT, 62% of cases presented in utero or in the first two days of life, many with second-degree AVB; in 39 fetuses studied by fetal magnetocardiography, AVB was rare in long QT types 1 and 2 (6%), but occurred in 7 of 12 fetuses with long QT type 3 or rare variants, with torsade de pointes in 3 of those 7, all with de novo variants [54]. In a meta-analysis of 83 studies with 265 fetuses with long QT, 2:1 block, torsade de pointes and absence of family history (de novo status) predicted high mortality [54]. Therefore, in the presence of fetal second-degree AVB, the editorial recommends identifying the aetiology and stratifying risk with the isovolumetric relaxation time, fetal magnetocardiography when available and genetic testing [54]. A 2026 review of the loci of paediatric AVB also associates neonatal long QT type 2 (KCNH2) with 2:1 block, describes a cycle in which bradycardia further prolongs the QT and favours early afterdepolarisations and torsade de pointes, and reports published infant mortality above 50% in this combination [58]. The 2021 PACES consensus accepts the pacemaker as adjunctive therapy in long QT with functional 2:1 block (class IIb) [16]. In differential practice, a fetal or neonatal 2:1 AVB with long QTc should point towards long QT syndrome and not towards a primary conduction disease [3, 54].

6.8. Comparative table

Table 6.1. Differential diagnosis of inherited atrioventricular block and conduction disease.

Table 6.1 summarises typical patterns without replacing individual assessment: cut-off ages are examples, and block level, when unclear from ECG and clinical context, can be determined by invasive electrophysiological study [4, 15].

7. Treatments and Risk Management Strategies

Management of inherited cardiac conduction disease has two aims: symptom relief and sudden death prevention. No pharmacological therapy yet arrests progression, and a pacemaker is indicated for symptomatic bradycardia and patients at high risk of complete AVB and sudden death [4]. Clinical Cardiogenetics emphasises that, apart from gene- and disease-specific differences (LMNA variants, muscular dystrophies), suspected or confirmed inherited CCD is managed as other aetiologies [4]. Clinically, geneticists make three management-changing contributions. First, identifying genotypes where a pacemaker alone is insufficient because ventricular arrhythmia risk is independent of bradycardia (LMNA, DES, SCN5A with Brugada phenotype, neuromuscular diseases). Second, recognising settings where guidelines allow earlier pacing than in degenerative disease because block is progressive and sometimes unpredictable. Third, guiding non-invasive measures: avoid conduction-slowing medicines, actively treat fever in SCN5A carriers and maintain serial surveillance [2–4].

The 2018 American guideline recommends (class I, level B-NR) assessing future ventricular arrhythmia risk and ICD need before any pacemaker implant [15]. Supporting text expressly names myotonic dystrophy and lamin A/C cardiomyopathy among symptomatic AVB settings where antitachycardia pacing or defibrillation capability may help. It also notes that ICDs have more complications than pacemakers and that, in some patients, prognosis is dominated by non-arrhythmic consequences of underlying disease [15]. This preliminary assessment underpins the following subsections. First, current guideline pacing indications and divergences are compared (7.1), followed by pacing mode and site (7.2), genotype-specific ICD indications, particularly LMNA (7.3), neuromuscular diseases (7.4) and congenital and paediatric AVB (7.5). Preventive and general pharmacological measures follow (7.6), then investigational therapies and regulatory status (7.7) and acute bradycardia treatment (7.8).

7.1. Permanent pacing indications: guideline comparison

No randomised trial has tested AVB pacing, but several observational studies show pacemakers prevent recurrent syncope and improve survival. Untreated AVB death results from both low-output heart failure and sudden death through prolonged asystole or bradycardia-triggered ventricular tachyarrhythmia [5]. Paroxysmal AVB has the same indications as permanent AVB because it shares syncope and sudden death risk and may progress to permanent block. However, reversible causes must be excluded and reflex forms recognised. Electrophysiologically documented infranodal block or onset triggered by extrasystoles or rate changes supports intrinsic infranodal AVB [5]. Table 7.1 compares guideline recommendations applicable to adults with inherited CCD. Neuromuscular and paediatric recommendations appear in 7.4 and 7.5 respectively.

Table 7.1. Permanent pacemaker indications in conduction disease (adults): recommendation class and evidence level by guideline.

Two methodological points matter. ESC 2021 recommends pacing asymptomatic narrow-QRS 2:1 AVB only if infranodal: pacing can be avoided with suspected supra-Hisian block (concomitant Wenckebach and disappearance during exercise) or electrophysiological demonstration [5]. American guidance applies I B-NR to acquired AVB and separately addresses neuromuscular disease, infiltrative cardiomyopathy and LMNA variants [15].

The most consequential divergence for geneticists concerns asymptomatic bifascicular block. ESC 2021 classifies pacing as contraindicated (III B) because only a minority develop AVB (1–2% annually) and implantation and late transvenous lead risks exceed benefit [5]. American guidance reaches the same conclusion for isolated conduction disease with 1:1 AV conduction (III: harm) [15]. The 2013 inherited arrhythmia syndrome consensus, however, explicitly excepts progressive conduction disease: it allows pacemakers (IIa) for bifascicular block with or without first-degree AVB, arguing that first-degree AVB plus bifascicular block and symptomatic advanced AVB carry substantial sudden death incidence. It acknowledges an exception to general recommendations [2]. Clinical Cardiogenetics adopts this option because of progressive disease [4]. The populations underlying the two positions differ. ESC's 1–2% annually concerns general bundle branch block populations, predominantly older and degenerative, and supporting data for the 2013 exception are not quantified there. Decisions in young pathogenic variant carriers should therefore be individual and shared, weighing age, documented progression rate, familial sudden death and cumulative lead complication risk over decades. ESC 2021 adds that pacing should be considered in neuromuscular disease because any fascicular block may progress unpredictably, even asymptomatically [5].

7.2. Pacing mode and physiological pacing

Pacing mode matters more in a young pathogenic variant carrier than an older patient with degeneration because pacemaker dependence may last decades and underlying disease may already include cardiomyopathy. In large parallel trials, dual-chamber pacing (DDD) did not outperform ventricular pacing for mortality. It does, however, prevent pacemaker syndrome, affecting up to one quarter of AVB patients in those trials, so ESC 2021 prefers it in AVB (IIa A) [5]. American guidance recommends dual-chamber over single-chamber ventricular pacing for sinus node dysfunction and AVB requiring pacing (I A). It accepts single-chamber ventricular pacing in selected patients without anticipated frequent ventricular pacing or with benefit-limiting comorbidities (I A) and recommends conversion to dual-chamber with pacemaker syndrome (I B-R) [15].

Chronic right ventricular pacing may be harmful. According to ESC 2021, pacing-induced cardiomyopathy occurs in 10–20% after 2–4 years of right ventricular pacing and associates with pacing burden above 20%, without a proven safe lower threshold [5]. The 2023 HRS/APHRS/LAHRS physiological pacing guideline cites a systematic review of 26 studies and approximately 58,000 patients: pooled prevalence was 12%, with 15 definitions, and incidence 5.9–39% over 0.7–16 years' follow-up [59]. It defines anticipated or documented right ventricular pacing of 20–40% or more as substantial [59]. These numbers concern general pacemaker populations, not genetic cohorts. No validated pacing-induced cardiomyopathy incidence estimate exists for SCN5A or TRPM4 carriers, and LMNA ventricular dysfunction may reflect disease itself.

Table 7.2. Physiological pacing (resynchronisation, His bundle or left bundle branch area pacing) in patients requiring pacemakers for AVB.

For inherited CCD, two points in the 2021 ESC guideline are particularly relevant. His bundle pacing can restore conduction in some high-grade AVB patients, but the anatomical advantage is lost with distal block, precisely the typical infra-Hisian pattern of SCN5A and TRPM4 forms [3–5]. Left bundle branch area pacing is being studied for these cases but, at guideline publication, data were scarce and long-term lead performance and extraction concerns precluded recommendations [5]. In the same guideline, leadless pacemakers are limited to VVI(R) or, more recently, VDD pacing, with AV synchrony 70–90% of the time. Absent long-term performance and end-of-life device data require particular consideration in young patients, for example with life expectancy above 20 years [5]. Finally, with simultaneous ICD and resynchronisation indications, CRT-D is recommended (I A) [5]. Thus, in LMNA and neuromuscular laminopathies, pacing site and defibrillation decisions are made together (7.3).

7.3. Implantable cardioverter-defibrillator: LMNA and other high-risk genotypes

In LMNA-associated CCD, pacemakers treat bradycardia but do not protect against sudden death. LMNA variants cause approximately 5–10% of dilated cardiomyopathies, and sinus node dysfunction and conduction disease often present first, frequently with preserved ventricular size and function [5]. ESC 2021 summarises evidence underlying ICD preference. In a mode-of-death meta-analysis, 46% dying suddenly had implanted pacemakers, and sudden death rates were similar with and without neuromuscular phenotypes. In two studies of carriers requiring pacing and implanted with ICDs, appropriate therapies occurred in 42% at 3 years and 52% at 5 years [5]. HRS 2022 describes both series. In the first, 8 of 19 carriers (42%) referred for pacemakers received appropriate shocks over mean follow-up 34 months. In the second, 11 of 21 carriers (52%) with prophylactic ICDs rather than pacemakers received appropriate therapy over 62 months, with inappropriate shocks in 7 of 21 (33%) and no sudden deaths [60]. These are small, pacing-indication-selected series, so percentages do not represent risk across all carriers.

Stratification has evolved from individual risk factors to a multivariable model. In a European registry of 269 carriers followed for median 43 months, 48 (18%) had a first malignant ventricular arrhythmia. Independent factors were non-sustained ventricular tachycardia, LVEF below 45% at first contact, male sex and non-missense variants, with events only in carriers with at least two factors [61]. Wahbi and colleagues' model was developed in 444 adults from a French national registry and externally validated in 145 patients from other centres, with life-threatening ventricular tachyarrhythmia in 19.3% and 23.4% respectively over median follow-up 3.6 and 5.1 years [62]. Predictors were male sex, non-missense variant, first-degree or greater AVB, non-sustained ventricular tachycardia and LVEF. C-index was 0.776 in derivation and 0.800 in validation, and an online calculator is available (https://lmna-risk-vta.fr) [62]. In the original paper, a ≥ 7% 5-year risk threshold captured 96.2% of events and achieved net reclassification of 28.8% of patients with events versus contemporary guidelines [62]. ESC 2022 adopted a different threshold, ≥ 10%, requiring an overt cardiac phenotype to avoid excessive implantation in phenotype-negative carriers [13].

Table 7.3. ICD or defibrillation-capable device indications in LMNA variant carriers.

The sources agree on the central principle: when an LMNA carrier needs pacing, the device should have defibrillation capability. They differ on thresholds without pacemaker indications, from qualitative 2013 risk factors to the 2022 calculator's 10% threshold [2, 13]. HRS 2022 added specific recommendations for laminopathies with myopathy (7.4) [60]. These apply to LMNA variant carriers with or without muscular dystrophy. In the risk studies, only 15–20% of patients had a diagnosis or family history of muscular dystrophy, and dystrophy was not an independent risk factor [60].

For other genotypes, ICD indications follow associated disease. Clinical Cardiogenetics recommends considering ICD in LMNA and DES carriers with severe CCD because of ventricular arrhythmia risk [4]. The 2026 Japanese review proposes ICD for CCD with ventricular arrhythmias in LMNA carriers with left ventricular dysfunction, DES-associated cardiomyopathy, mitochondrial diseases and SCN5A carriers surviving cardiac arrest or with spontaneous sustained ventricular tachycardia. In Brugada overlap, syndrome-specific criteria apply [3]. In loss-of-function SCN5A carriers, arrhythmic event rate in the multicentre cohort of 615 was 0.7% annually, with clinical predictors helping individualise decisions (section 11.2) [41].

7.4. Neuromuscular diseases

In neuromuscular diseases involving conduction (myotonic dystrophy types 1 and 2, Emery–Dreifuss, limb-girdle type 1B and mitochondrial cytopathies such as Kearns–Sayre), guidelines recommend earlier pacing than in degenerative CCD because progression is unpredictable [5, 15, 16, 60]. All four sources add the same proviso: whenever pacing is indicated, consider ICD or resynchronisation, respecting care goals and expected meaningful survival above 1 year [5, 15, 60].

Myotonic dystrophy type 1. Supporting evidence is observational. Up to 20% have ECG AVB or intermittent second- or third-degree AVB on 24-hour Holter. More than 50% with normal ECG may have infra-Hisian block electrophysiologically, and in one study 46.7% with HV ≥ 70 ms developed high-grade AVB [15]. A large retrospective study showed 75% lower sudden death risk with pacemakers [15]. In a single-centre series of 211, 45 had severe electrocardiographic abnormalities (PR > 240 ms, QRS > 120 ms, second- or third-degree AVB or non-sinus rhythm), of whom 29 (65%) received pacemakers or ICDs. More than 90% were asymptomatic at implantation, and at 5 years 13% were pacemaker-dependent [15]. In a prospective multicentre registry, severe abnormalities predicted sudden death with 74% sensitivity and 97.1% negative predictive value. Sudden death caused 33% of deaths and neuromuscular respiratory failure 40%, supporting device selection according to arrhythmic profile, patient preference and overall prognosis [15].

Table 7.4. Pacing and ICD in myotonic dystrophy: classes by guideline.

The main divergence concerns moderate conduction abnormality (PR ≥ 240 ms or QRS ≥ 120 ms). European and American adult guidelines assign IIb, whereas the 2021 paediatric and 2022 HRS neuromuscular consensuses raise this to IIa [5, 15, 16, 60]. With HV ≥ 70 ms, the hierarchy reverses: class I in ESC 2021 and ACC/AHA/HRS 2018, IIa in HRS 2022 [5, 15, 60]. HRS 2022 also recommends close arrhythmic complication surveillance with mexiletine or other sodium channel blockers in myotonic dystrophy with CCD (I C-LD). It recommends ECG, Holter and imaging assessment at diagnosis, repeated periodically even asymptomatically (I B-NR) [60].

Emery–Dreifuss and limb-girdle dystrophy type 1B. These X-linked (EMD) or autosomal dominant (LMNA) forms combine high bradyarrhythmia and ventricular tachyarrhythmia risks. Sudden death risk is probably greater in LMNA than X-linked disease [60]. In an observational study of 41 LMNA carriers, PR ≥ 230 ms distinguished those with and without ventricular arrhythmia with 87% sensitivity and specificity [60]. Accordingly, the 2022 consensus sets ICD thresholds using conduction markers rather than LVEF alone. It recommends ICD (I B-NR) with second- or third-degree AVB, PR ≥ 230 ms or spontaneous HV ≥ 70 ms. It considers ICD reasonable (IIa C-LD) with LBBB, RBBB or atrial fibrillation or flutter with ventricular response below 50/min, and also LVEF < 45% and non-sustained ventricular tachycardia (IIa B-NR). It allows consideration (IIb C-LD) for symptomatic sinus node dysfunction or sinus rate below 40/min [60]. An implanted ICD should be pacing-capable (I B-NR). Transvenous ICD is preferable to subcutaneous because of high future pacing likelihood and bradycardia- or pause-dependent tachyarrhythmia risk [60]. If ICD conflicts with care goals, pacemaker or appropriate resynchronisation without defibrillation is recommended (I C-EO). Resynchronisation is recommended (I B-NR) with LVEF ≤ 35%, LBBB, QRS ≥ 150 ms and class II–IV symptoms, suspected right-ventricular-pacing-induced cardiomyopathy or anticipated right ventricular pacing ≥ 40% [60]. As atrial standstill is prominent in Emery–Dreifuss dystrophy, anticoagulation is recommended (I B-NR) for atrial fibrillation or flutter and atrial standstill after weighing bleeding risk [60]. PR thresholds differ: ≥ 230 ms alone in HRS 2022 versus > 240 ms with LBBB in ACC/AHA/HRS 2018 and > 240 ms and/or LBBB in paediatric consensus [15, 16, 60].

Kearns–Sayre syndrome and mitochondrial cytopathies. Conduction disease is the commonest Kearns–Sayre cardiac manifestation and may progress to complete AVB and sudden death [5]. Recommendations are among the most permissive in pacing. ESC 2021 considers pacing with prolonged PR, any AVB degree, bundle branch or fascicular block (IIa C), allowing prophylaxis even without conduction abnormalities (IIb C) [5]. American guidance considers it reasonable with any conduction abnormality (IIa C-LD) and recommended with second- or third-degree AVB or HV ≥ 70 ms (I B-NR) [15]. Paediatric consensus indicates pacing with any AVB degree including first degree or any conduction abnormality (I C-LD) [16]. The 2022 neuromuscular consensus considers it reasonable in mitochondrial cytopathies with progressive AV or fascicular conduction abnormality of any degree (IIa B-NR) [60].

Shared decisions and end of life. HRS 2022 provides dedicated recommendations, all I C-EO unless specified, for patients whose survival may be limited by respiratory failure. It recommends periodically discussing device function and deactivation, choosing pacemaker versus ICD according to overall goals and discussing non-replacement or shock deactivation in advance care planning. It considers honouring requests to deactivate pacing at end of life reasonable (IIa C-EO) after explaining consequences [60]. Surveillance and follow-up criteria appear in section 11.

7.5. Congenital and childhood-onset atrioventricular block

Isolated congenital complete AVB, immune or non-immune, and childhood-onset AVB have specific pacing criteria. PACES 2021 recommends pacemakers (I) for symptomatic bradycardia (B-NR), wide-QRS escape rhythm, complex ventricular ectopy or ventricular dysfunction (B-NR). It also recommends them in asymptomatic newborns or infants with mean ventricular rate ≤ 50/min (C-LD), cautioning that rate alone should not be the criterion because low output may occur at higher rates [16]. After age one, pacing is reasonable (IIa B-NR) in asymptomatic children with mean rate below 50/min or prolonged pauses, and left ventricular dilatation (z ≥ 3) with significant mitral regurgitation or systolic dysfunction (IIa C-LD). It may be considered (IIb C-LD) in asymptomatic adolescents with acceptable rate, narrow QRS and normal function after individual assessment [16]. The document emphasises infant decisions also depend on weight, ventricular function and comorbidities, and rate criteria should use consistent measurements rather than one recording. Contemporary studies show approximately 66% of newborns and infants with isolated congenital complete AVB receive pacemakers within one year and 90% by age 20 [16]. Without pacing, natural history includes progressive left ventricular dysfunction, mitral regurgitation and cardiovascular mortality in the fourth or fifth decade. Some paced patients still develop cardiomyopathy through antibody-mediated myocarditis or pacing-induced dyssynchrony [16].

ESC 2021 recommends pacing congenital complete or high-grade AVB (I C) with symptoms, pauses exceeding three escape cycles, wide-QRS escape, long QT, complex ventricular ectopy or mean daytime rate below 50/min. It allows pacing without these factors (IIb C), acknowledging divergent benefit opinions [5]. The same factors guide decisions in pregnant women with congenital complete AVB; pregnancy implantation criteria and technique appear in section 8.5 [5]. In children with genetic progressive conduction disease, PACES 2021 allows pacemakers (IIb C-LD) even with normal AV conduction if rapid AV node deterioration is possible, considering age, size and individual factors [16]. Small-child implantation, often epicardial, and long-term follow-up appear in PACES [16]. The French childhood non-immune AVB cohort in sections 3 and 11 documents frequent long-term implantation [12].

7.6. Medicines to avoid, fever and general measures

No medicine arrests inherited CCD progression [4]. Pharmacological measures are therefore preventive: avoid aggravating conduction and treat arrhythmic triggers. The 2013 consensus recommends restricting conduction-slowing medicines in asymptomatic familial variant carriers. It also recommends preventive fever treatment because fever aggravates SCN5A disease [2]. Clinical Cardiogenetics extends the first recommendation to all overt CCD and loss-of-function SCN5A carriers, referring to www.brugadadrugs.org for medicines to avoid [4]. Its Table 17.2 summarises gene-specific measures: avoid sodium channel blockers and treat fever in SCN5A forms, with usual CCD management in TRPM4, NKX2-5 and TBX5 [4]. The 2026 review recommends active antipyretic treatment in SCN5A CCD to prevent fever-triggered ventricular arrhythmias, as in Brugada syndrome. It notes that cilostazol and milrinone, described as beneficial in Brugada, have no proven conduction-defect efficacy [3].

In LMNA cardiomyopathy, GeneReviews recommends avoiding block-aggravating medicines such as beta-blockers and calcium channel blockers until pacemaker or ICD implantation [17]. This creates a real therapeutic conflict because beta-blockers form part of standard dilated cardiomyopathy treatment and ventricular rate control is part of chronic atrial fibrillation treatment [17]. American 2018 guidance partly resolves this by recommending pacemakers (I C-LD) for symptomatic AVB caused by clinically necessary guideline-directed treatment without alternatives [15]. In myotonic dystrophy, mexiletine and other sodium channel blockers used for myotonia require close arrhythmic complication surveillance with CCD (I C-LD) [60]. Reversible conduction defect causes to exclude and correct before attributing progression to genetics include beta-blockers, calcium and sodium channel blockers, digoxin and amiodarone, hyperkalaemia, hypothermia and thyroid dysfunction according to Clinical Cardiogenetics [4].

Non-pharmacological measures complete management. High-intensity exercise and competitive sport are not recommended in LMNA carriers with cardiomyopathy (III C) [13]. Patients should seek immediate care after syncope to assess urgent pacemaker need [4]. ECG and echocardiographic surveillance is individualised by severity, progression rate, symptoms and age, with closer monitoring in muscular dystrophies; details appear in section 11 [4]. In fever or active infection, ESC 2021 recommends deferring permanent implantation until at least 24 hours afebrile. If immediate pacing is needed, temporary transvenous pacing via jugular or axillary/lateral subclavian access is preferred. Fever within 24 hours before implantation (OR 5.83) and previous temporary pacing (OR 2.46) were associated with device infection in a prospective study of 6319 patients [5].

7.7. Investigational therapies and regulatory status

No disease-modifying treatment is approved for inherited CCD. The most advanced attempts target LMNA cardiomyopathy rather than conduction defects specifically and should be separated by development phase. The selective p38α MAPK inhibitor ARRY-371797 (PF-07265803), associated with improved 6-minute walk performance in phase 2, was tested in phase 3 REALM-DCM (NCT03439514). It included 77 patients aged 23–72 with LMNA variants, class II–III symptoms, LVEF ≤ 50% and implanted ICDs, randomised to 400 mg twice daily or placebo. The trial stopped at interim analysis for futility: median 24-week walk difference was 4.9 m (95% CI −24.2 to 34.1; p = 0.82), without quality-of-life, NT-proBNP or composite outcome differences or new safety signals [63]. NVC-001, an adeno-associated virus serotype 9 vector expressing a dominant-negative SUN1 transgene, is in first-in-human development. It is being studied in phase 1/2 SUNBEAM-LMNA (NCT07606274), an open-label multicentre single-intravenous-dose study at three levels in adults with LMNA dilated cardiomyopathy. Nuevocor sponsors it, actual start was 16 June 2026, estimated enrolment 21, centres are in the USA, the primary outcome is safety and primary completion is expected March 2030. No results are published [64]. Preclinically, a 2026 knock-in mouse study of nonsense LMNA-R225X identified in a progressive AVB family found reduced calcium-activated potassium channel SK3 in the AV node. Pharmacological SK3 activation attenuated AVB in LMNA deficiency models, proposing a target without human study [33]. ClinicalTrials.gov searches for this article using progressive conduction disease, TRPM4, Lenègre disease and inherited AVB terms found no therapeutic trial targeting SCN5A or TRPM4 forms. Negative searches do not prove trials absent [65].

Table 7.5. Regulatory status of medicines cited in this article (USA and European Union), accessed October 2026.

Devices (pacemakers, ICDs, resynchronisation and leadless systems) are the only effective inherited CCD therapy. Their indications derive from guidelines summarised in 7.1–7.5 rather than disease-specific labelling [4].

7.8. Acute treatment of atrioventricular block-related bradycardia

Acute management of symptomatic or haemodynamically compromising AVB starts by identifying and removing causes, followed by medical treatment as a bridge to pacing [15]. For geneticists, block level is decisive. Nodal AVB responds better to autonomic manipulation with atropine, isoproterenol or adrenaline. Intra- or infra-Hisian AVB may progress rapidly and unexpectedly, has slower, unpredictable escape, does not respond to atropine and sometimes improves with catecholamines [15]. This is expected in inherited CCD, where AVB is typically type II, paroxysmal or complete with prolonged HV [3]. Atropine is unlikely to improve His or His–Purkinje block. Worsened conduction or haemodynamic compromise has been reported, so caution is needed with wide-QRS AVB suggesting significant His–Purkinje disease [15].

American guidance considers atropine reasonable (IIa C-LD) for presumed nodal second- or third-degree AVB with symptoms or haemodynamic compromise. Beta-adrenergic agonists (isoproterenol, dopamine, dobutamine or adrenaline) may be considered (IIb B-NR) for symptomatic second- or third-degree AVB with low coronary ischaemia likelihood [15]. In a small prehospital randomised trial of unstable bradycardia unresponsive to atropine, dopamine equalled transcutaneous pacing. Beta-agonist adverse effects include ventricular arrhythmias and coronary ischaemia, and isoproterenol may worsen hypotension through vasodilatation [15]. Table 7.6 reproduces guideline Table 8 doses for symptomatic bradycardia from sinus node dysfunction or AVB.

Table 7.6. Medicines for symptomatic bradycardia from sinus node dysfunction or AVB, using ACC/AHA/HRS 2018 Table 8 doses [15]; labelling status from Table 7.5.

The guideline table refers to adults. Label doses and indications vary between manufacturers; in the EU, these drugs have national authorisations, and the last column uses the Portuguese SmPCs of atropine (Atropina Basi®) and isoprenaline (Isoprenalina Macure®) as an example (7.7). The 2021 ESC guideline recommends considering chronotropic medication before starting temporary pacing, taking into account adverse effects, contraindications and interactions. In inflammatory diseases complicated by AVB, it admits intravenous isoprenaline or temporary pacing as a bridge to specific therapy [5].

For temporary pacing, American guidance considers transvenous pacing reasonable (IIa B-NR) for second- or third-degree AVB with symptoms or haemodynamic compromise refractory to medication. If prolonged temporary pacing is required, it prefers an externalised active-fixation permanent lead to a passive-fixation temporary lead (IIa B-NR). Transcutaneous pacing may be considered (IIb B-R) until transvenous or permanent placement or bradyarrhythmia resolution [15]. ESC 2021 is more restrictive. It requests avoiding temporary transvenous pacing whenever possible and minimising duration, reserving it for severe bradyarrhythmia with syncope or haemodynamic compromise and reversible indications, or bridging when permanent implantation is not immediately possible. If permanent criteria are met, implantation should be prompt [5]. Caution reflects procedural and immobilisation complications and association between prior temporary pacing and permanent-device infection (OR 2.46). Jugular access is preferable when planning an ipsilateral permanent device. Transcutaneous pacing, rapid but less stable and requiring continuous sedation, is reserved for emergencies with close haemodynamic surveillance [5]. In inherited CCD with high-grade AVB, pacing need should be treated as permanent because disease progresses without a reversible cause. Temporary pacing only bridges to a genotype-selected permanent device with or without defibrillation (7.3–7.4) [4, 5].

8. Reproductive Options and Family Counselling

8.1. Inheritance, penetrance and recurrence risks

Most congenital and inherited progressive conduction diseases follow autosomal dominant inheritance; autosomal recessive or sporadic cases, X-linked forms in myopathy-associated conduction disease (DES, DMD, LAMP2, EMD) and maternal, autosomal or sporadic mitochondrial transmission occur [3, 49]. The 2022 EHRA/HRS/APHRS/LAHRS consensus recommends pretest genetic counselling. Families should understand that autosomal dominant transmission probability is 50% each pregnancy irrespective of sex and that carrying a P/LP variant does not necessarily mean clinical disease [10]. ESC 2025 pregnancy guidance reiterates that most inherited heart diseases are autosomal dominant with 50% transmission risk [74].

Penetrance and expressivity vary by gene and age, making counselling difficult more than transmission risk. Cardiac laminopathy penetrance is age-dependent, beginning in the third and fourth decades and considered above 90–95% by the seventh; nevertheless, onset age, severity and course cannot be predicted in a carrier child or sibling [17]. In TRPM4 forms, onset and severity vary within families and penetrance is incomplete [4, 9]. The 28% conduction disease among 25 P/LP carriers in UK Biobank, all diagnosed after age 50 (section 2.8), derives from an unselected predominantly European adult population and cannot represent penetrance in phenotype-selected families [40]. In Holt–Oram syndrome penetrance is usually complete but rare reduced-penetrance families exist; intrafamilial limb and cardiac malformation variability is substantial and an affected child's phenotype unpredictable [36].

Parental assessment of an apparently isolated case is mandatory before risk estimation. The laminopathy GeneReview recommends history, examination, echocardiography and parental ECGs plus familial variant testing because an asymptomatic parent may be heterozygous; both lineages should be considered because families with maternal and paternal dilated cardiomyopathy have been described [17]. If neither parent's leucocyte DNA contains the variant with biological parentage confirmed, consider a de novo variant and parental germline mosaicism; GeneReviews estimates sibling recurrence at approximately 1% [17]. In Holt–Oram syndrome, up to 60% are isolated, and de novo occurrence can be asserted only after excluding the variant molecularly in both parents; a somatic and gonadal mosaic parent may have mild features [36]. In the French cohort of children with isolated non-immune AVB, 78 of 204 parents with ECGs (38.2%) had conduction abnormalities and a 56-year-old father had undiagnosed complete AVB. Absent parental symptoms therefore do not exclude familial disease [12]. Table 8.1 summarises recurrence risks.

Table 8.1. Transmission and recurrence risks by family setting.

8.2. Cascade family screening and follow-up intervals

Long-term familial conduction disease data are scarce. Clinical Cardiogenetics therefore proposes no rigid algorithm but individualised patient and family follow-up according to pathogenic variant identification and familial or sporadic disease [4]. The 2022 consensus recommends targeted clinical and genetic family investigation, “family cascade”, in families with a P/LP variant in a validated conduction disease gene, including full pedigree evaluation [10]. ESC 2021 considers relative genetic testing after a phenotype-explaining pathogenic variant is identified in the index case (class IIa, level C), with regular asymptomatic carrier follow-up for symptoms, worsening conduction and emerging heart failure [5]. American 2018 guidance recommends genetic counselling and familial variant testing in first-degree relatives after identification of a causal index-case variant (class I, level C-EO), allowing targeted testing with counselling to facilitate cascade screening during inherited conduction disease diagnosis (IIb, C-EO); asymptomatic carriers and untested first-degree relatives should receive regular follow-up [15].

With an index-case pathogenic variant, Clinical Cardiogenetics recommends familial variant testing. Carriers undergo a complete baseline cardiac assessment with symptom review, examination, ECG and echocardiography; exercise testing, Holter or event recorders are added for intermittent symptoms [4]. Because disease progresses, carriers should be reassessed periodically, for example every 1–3 years according to age and ECG abnormalities, with symptom review and ECG; echocardiography every 1–2 years is suggested in LMNA carriers [4]. GeneReviews specifies laminopathy follow-up: cardiovascular assessment with ECG, 24–48-hour rhythm monitoring and left ventricular function at least annually for any ECG abnormality, and history, examination, echocardiography and ECG every 1–2 years or with new symptoms in asymptomatic carriers [17]. In Holt–Oram syndrome, GeneReviews recommends annual ECG for those at conduction-defect risk and annual ECG plus Holter with established conduction disease to assess progression [36]. All carriers should seek urgent care after syncope [4].

Variant-negative relatives may be reassured unless variant pathogenicity is doubtful; Clinical Cardiogenetics still advises a baseline ECG and more extensive assessment for symptoms [4]. The 2022 consensus considers surveillance unnecessary for non-carriers and their descendants [10]. GeneReviews adds caution: because variants in multiple dilated cardiomyopathy genes may coexist in one family, discharge should follow individual clinical, genetic and family-history evaluation [17]. A variant of uncertain significance not reclassified as likely pathogenic should not guide cascade screening; clinical screening is used instead [10].

In families without an identified variant, the strategy depends on the family history. In unexplained conduction disease in a young patient without evident familial disease, first-degree relatives have a baseline ECG, and also an echocardiogram if the index case has structural heart disease; if the assessment is normal, they may be discharged, with instructions to seek attention in the event of presyncope, syncope or exercise intolerance [4]. When the disease is familial but testing is negative, extended testing with cosegregation analysis should be considered. First-degree relatives are screened in the same way, but even with a normal assessment it is probably prudent to follow them periodically for a long time, unless the affected members of the family had onset at a young age [4]. In the context of laminopathy without possible molecular testing, GeneReviews recommends annual assessment of first-degree relatives with history, physical examination, echocardiogram and ECG, because a normal baseline examination does not exclude the disease [17]. In Holt-Oram syndrome with an unknown variant, assessment of relatives includes echocardiography, ECG and hand radiography [36]. In relatives of children with isolated non-immune AVB, the French authors advocate considering a panel of arrhythmia and cardiomyopathy genes in all children with conduction disease whose mothers are negative for anti-Ro/SSA, followed by family cascade testing if the result is positive [12].

8.3. Predictive testing in children

Timing of predictive testing in asymptomatic children shows the greatest source divergence because it depends on gene-attributed risk. ESC 2021 allows deferring variant-specific testing in asymptomatic children because conduction diseases are age-dependent with incomplete penetrance, emphasising individual assessment by variant risk [5]. The 2022 consensus states that asymptomatic first-decade children do not strictly need genetic-status investigation, although earlier assessment may be relevant in specific settings, and recommends that predictive testing may be considered in specific conduction disease contexts (expert opinion) [10]. American 2018 guidance likewise allows deferral in asymptomatic children [15].

Laminopathy is the most relevant exception, because the risk of sudden death often precedes ventricular dysfunction. GeneReviews estimates the probability of a detectable clinical presentation of LMNA cardiomyopathy in children at about 1.4%; although low, it recommends offering testing, because it allows identification of at-risk children who may benefit from early treatment. It further recommends stricter clinical screening in families with aggressive early-onset disease and testing of symptomatic individuals at any age [17]. Predictive testing should be performed only in the context of formal genetic counselling, and it does not predict age at onset, severity or rate of progression [17]. In families with an SCN5A variant in which Brugada syndrome phenotypes coexist, the same consensus's recommendation for that syndrome applies, which admits predictive testing in children from birth [10].

Clinically, decisions weigh gene and variant, relatives' onset and severity, interventions changing childhood management and parental preferences. The joint American Academy of Pediatrics and American College of Medical Genetics and Genomics policy cited by GeneReviews addresses ethical issues in minors [17]. If testing is deferred, at-risk children should continue clinical ECG assessment because screening may detect block and syncope requires urgent evaluation [4]. In the French cohort of 385 isolated non-immune childhood AVB cases, 81.6% were asymptomatic at diagnosis and one fetus was diagnosed through family screening because a sibling had isolated complete AVB at age 5 [12].

8.4. Reproductive planning, prenatal diagnosis and preimplantation genetic testing

Genetic risk determination and discussion of prenatal and preimplantation testing should precede pregnancy. Decisions on testing asymptomatic at-risk relatives are also best made beforehand. Offspring risk counselling and reproductive options should be offered to affected or at-risk young adults [17, 36]. ESC 2025 recommends cardiovascular genetic testing before pregnancy at a specialist cardiogenetics centre or network model with multidisciplinary care and pre- and post-test counselling, and timely preimplantation and prenatal discussion with all women or couples with a known parental monogenic or chromosomal alteration [74]. Many options take time and require early referral, and decisions should consider cultural, religious and legal aspects and access within local ethical and legal frameworks ensuring autonomous choice [74].

In ESC 2025's preconception counselling figure (Figure 4, visually read), genetic yield is 15–90% in channelopathies with moderate gene or variant impact on pregnancy management, and 30–60% in cardiomyopathies with mild impact [74]. Isolated progressive conduction disease is not a separate category. Table 8.2 summarises reproductive options.

Table 8.2. Preimplantation, prenatal and postnatal diagnostic options.

Prenatal and preimplantation testing are possible after identifying familial pathogenic LMNA or TBX5 variants [17, 36]. In Holt–Oram, a positive fetal molecular result should prompt detailed ultrasound because variable expression prevents genotype-only prediction of upper limb and cardiac malformation severity [36]. In age-dependent, incompletely penetrant conduction disease, prenatal results likewise establish carrier status rather than onset age or severity [17]. Professional and family perspectives on prenatal diagnosis differ; most centres consider it a personal decision, but discussion is useful [17, 36]. Prenatal and preimplantation options require a familial P/LP variant; the 2022 consensus excludes unreclassified uncertain variants from cascade screening, and GeneReviews states uncertain variants neither establish nor exclude diagnosis [10, 17].

ESC 2025 states that infertility in women with cardiovascular disease is generally similar to the population and assisted reproduction requests should not be denied on presumed cardiovascular risk before multidisciplinary discussion [74]. It recommends single embryo transfer because multiple pregnancy increases cardiovascular changes and maternal and fetal complications, individual assessment of ovarian-stimulation-related venous thromboembolism risk and avoidance of fertility treatment in mWHO 2.0 class IV conditions [74]. Without molecular diagnosis, the Holt–Oram GeneReview suggests considering index-case DNA storage for future reanalysis as methods and knowledge develop [36].

8.5. Pregnancy in women with inherited conduction disease

ESC 2025 classifies maternal risk through modified World Health Organization mWHO 2.0. Bradycardia requiring a pacemaker is class II, as are most supraventricular arrhythmias. Dilated or non-dilated cardiomyopathy with normal or mildly reduced left ventricular function (ejection fraction >45%) is class II–III, ejection fraction 30–45% class III and ejection fraction <30% or NYHA III/IV class IV. Unrepaired uncomplicated atrial or ventricular septal defect is class II, and repaired without significant residual lesions class I [74]. Mobitz I second-degree AVB is common in pregnancy and rarely progresses. No data describe congenital AVB progression during pregnancy, and vaginal delivery adds no risk in asymptomatic, haemodynamically stable women with normal cardiac anatomy and function. Prophylactic temporary pacing leads are usually not indicated and require individual decisions [74].

ESC 2025 Recommendation Table 17, visually read, does not recommend prophylactic temporary pacemakers during delivery (class III, level C) in asymptomatic congenital AVB with normal anatomy and function, narrow QRS and ventricular rate ≥50/min [74]. ESC 2021 pacing guidance adds that with stable narrow-QRS junctional escape, pacemakers may be unnecessary or deferred until postpartum without risk factors: syncope, pauses exceeding three escape cycles, wide-QRS escape, prolonged QT, complex ventricular ectopy or mean daytime rate below 50/min. Complete AVB with slow wide-QRS escape should prompt pregnancy pacemaker implantation [5]. Pacemaker implantation is safe during pregnancy, particularly after gestational week 8, with minimal fluoroscopy or echocardiographic or electroanatomical guidance [5, 74]. ESC 2025 states temporary and permanent pacing indications do not differ from non-pregnant women [74]. Life-threatening acute bradycardia is treated as outside pregnancy; isoproterenol may be used when benefits exceed risks, and breast milk excretion is unknown [74].

For women with pacemakers or ICDs, ESC 2025 Figure 17, visually read, includes an electrophysiologist in the Pregnancy Heart Team from preconception and pregnancy device assessment (battery, sensing, thresholds, lead impedance and stored arrhythmic episodes) with regular visits [74]. During delivery it provides continuous rhythm monitoring in high-risk women and deactivation of the ICD ventricular tachycardia therapy zone, retaining only fibrillation, or a magnet over the generator. In pacing-dependent patients, bipolar electrosurgery should be used and DOO or VOO modes should not be programmed because of R-on-T risk. Devices are restored to original parameters postpartum [74]. Predelivery ICD interrogation is recommended and usual device follow-up should continue during pregnancy [74].

Sources differ on laminopathy. GeneReviews, updated in 2022, considers pregnancy contraindicated in dilated cardiomyopathy because of significantly increased maternal mortality, recommending high-risk obstetric follow-up if pregnancy occurs [17]. More recent ESC 2025 applies no blanket contraindication: it stratifies by mWHO 2.0 and high-risk criteria (severe systolic dysfunction, NYHA III/IV, right ventricular failure, sustained ventricular arrhythmias, atrial fibrillation, severe mitral regurgitation), considering uncomplicated pregnancy likely with mild dysfunction, good functional capacity and no arrhythmias or prior events [74]. In a retrospective cohort of 89 female P/LP LMNA carriers, 60 with previous pregnancy, followed for median 5 years, pregnancy number was not associated with greater atrial fibrillation, AVB, sustained ventricular arrhythmia or device implantation risk or faster ejection fraction decline. Arrhythmias occurred in 9% of pregnancies without increased maternal and fetal complications [76]. This small observational study does not exclude risk with advanced disease. ESC 2025 recommends indicated ICD implantation before pregnancy, and GeneReviews recommends preconception cardiovascular assessment and genetic counselling in at-risk women of unknown genetic status [17, 74].

In carriers of SCN5A variants with a Brugada phenotype, the 2025 ESC guideline recommends avoiding contraindicated drugs, large meals and excess alcohol and treating fever and its causes promptly; it considers quinidine if there are symptoms during pregnancy [74]. In Holt-Oram syndrome, pregnant women with a known structural defect or conduction abnormality should be followed by a multidisciplinary team including cardiology, and those who have never had a cardiac assessment should have one before pregnancy or as soon as it is recognised [36]. In families with a primary arrhythmia, the fetal heart rate should be assessed at each antenatal visit and compared with the norms for gestational age, because the fetus may manifest the arrhythmia [74]. The association between fetal bradycardia and the familial variant is illustrated by the case of fetal AVB with a TRPM4 variant described in section 10 [52].

8.6. Counselling in maternal autoimmune congenital atrioventricular block

Maternal-antibody-mediated congenital block is not inherited but recurs in siblings. The first counselling step after fetal or neonatal AVB is therefore distinguishing this from genetic disease. Approximately 90–95% of isolated AVB diagnosed before 6 months results from transplacental maternal anti-Ro/SSA, alone or with anti-La/SSB, causing AV nodal inflammation and fibrosis and irreversible complete block [12]. The 2020 American College of Rheumatology (ACR) reproductive health guideline in rheumatic and musculoskeletal diseases estimates complete AVB in approximately 2% of pregnancies with anti-Ro/SSA or anti-La/SSB without prior neonatal lupus and 13–18% after a child with cutaneous or cardiac neonatal lupus [75]. Low titres probably do not confer the same risk as high titres, complete AVB rarely develops after 26 weeks, approximately 20% of affected children die in utero or in the first year and more than half need pacemakers [75]. The 20–40% maternal lupus value in the Oxford Desk Reference, without defined denominator (section 6.4), does not correspond to these estimates used here [56, 75].

ACR 2020 recommendations for anti-Ro/SSA- or anti-La/SSB-positive pregnancy, read in the full text and Table 4, are summarised in Table 8.3 [75].

Table 8.3. ACR 2020 recommendations in anti-Ro/SSA- or anti-La/SSB-positive pregnancy.

The ACR bases hydroxychloroquine on early and limited data and on the low risk of the drug [75]. The guideline does not set the dose, and the benefit of dexamethasone in first- and second-degree block is controversial [75]. The oral dexamethasone label does not include fetal therapy; the guideline dose of 4 mg/day lies within the label's general initial dosage range in adults (0.75–9 mg/day, depending on the disease), which constitutes extrapolation and off-label use [77]. The main prospective evidence is the PATCH trial, a phase 2, open-label, single-arm study described in section 6.5: with hydroxychloroquine 400 mg/day, started by the end of the 10th week of gestation and continued until delivery, recurrence of second- or third-degree AVB was 7.4%, compared with a historical rate of 18%, in a design without randomisation or concurrent control [14]. The São Paulo cohort, also described in section 6.5, associated complete AVB with higher maternal titres and less use of hydroxychloroquine before conception, with titre thresholds dependent on the laboratory method [55]. Prevention of congenital AVB is not among the indications of the US Plaquenil label (malaria, rheumatoid arthritis, systemic lupus erythematosus and discoid lupus), so it is a use outside the approved indication [78]. The PATCH dose (400 mg/day) coincides with the label dose in adult systemic lupus erythematosus (200 mg or 400 mg per day, in one or two doses, i.e. up to 400 mg/day), an analogous condition [78]. For retinal toxicity, the American Academy of Ophthalmology maintains in its 2025 revision the maximum daily dose of 5.0 mg/kg of real body weight, not exceeding 400 mg/day in severe obesity, and recommends a baseline examination with OCT and autofluorescence soon after initiation and annual screening, which may be deferred during the first 5 years in the absence of risk factors (kidney disease, tamoxifen, onset at an older age) [79, 80]; at 400 mg/day, this limit is only respected from 80 kg of real body weight, so in lighter pregnant women the fixed PATCH dose exceeds it during gestation.

The family message has two parts. With maternal antibodies, recurrence is non-Mendelian: approximately 2% or 13–18% as above, with hydroxychloroquine apparently reducing recurrence [14, 75]. With maternal anti-Ro/SSA negativity, isolated childhood AVB should prompt genetic consideration using arrhythmia and cardiomyopathy panels, parental ECGs and cascade if positive [4, 12]. When the pregnant woman herself has congenital AVB, section 8.5 applies [74].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what is known and unknown

True inherited progressive conduction disease frequency is unknown. The 2026 review emphasises current estimates predominantly derive from pacemaker implantation, introducing bias. Disease is probably underdiagnosed in young people, frequently classified as degenerative and highly age-dependent, so numbers represent approximate burden rather than true prevalence [3]. Orphanet records approximately 50 cases or families worldwide for ORPHA:871 and unknown point prevalence category [1]. This reflects published families rather than population frequency.

Available data have differing denominators and are not directly comparable, as Table 9.1 shows.

Table 9.1. Available frequency indicators with population, denominator and limitations.

The 2026 review interprets Gourraud's values as the proportion (0.21–2.28%) of pacemaker patients suspected of progressive conduction disease and uses this for the Japanese estimate [3]. The original abstract describes mapped birthplace disease frequency without specifying denominator [81]. Full French study text was not consulted, so 0.0005% annually should be treated only as an order of magnitude. The robust French finding is different: geographical frequency heterogeneity identified five large progressive conduction disease families and three phenotypic patterns in the highest-frequency parishes [81].

Age dependence dominates epidemiology: bundle branch block and pacemaker prevalence rise sharply after age 50–65, and only 5% of Japanese hospital AVB implants occurred before age 50 (section 4) [3, 4]. Relative rarity in young people underpins the age-50 threshold in definitions and testing indications (section 5).

Sex-specific data are scarce. In the French cohort of 385 isolated non-immune childhood AVB patients, 49.9% were boys [12]. In SCN5A carriers followed in 2025, male sex independently predicted arrhythmic events and asymptomatic women with QRS below 100 ms had none [41]. X-linked Emery–Dreifuss heterozygotes may develop cardiac disease, generally after age 50 [50].

9.2. Founder populations and geographical clustering

Much inherited conduction disease knowledge comes from large families and founder populations. In these populations, one variant explains a disproportionate fraction, affecting testing choice and family screening (Table 9.2).

Table 9.2. Founder populations and geographical clustering.

The Dutch founder effect explains why approximately 30% testing yield in the Netherlands cannot be transferred elsewhere. In the French paediatric cohort, for example, only 5.3% tested had P/LP variants [4, 12]. In Iceland, genomic study authors proposed NKX2-5 variant testing in dilated cardiomyopathy patients and relatives and carrier monitoring [46]. GeneGuidance notes this genotype-based value is not comparable with Orphanet's clinical atrial-septal-defect-with-conduction-defects count (11 cases). They measure different things: genotype-identified founder variant carriers versus clinically identified syndrome patients [9, 82]. The Icelandic variant's DNA-level description is omitted because it was not confirmed in the consulted source.

African, South Asian and Latin American ancestry data are scarce in consulted sources. UK Biobank, the largest population analysis, was 94.7% European ancestry, and authors repeated analyses restricted to this ancestry because variants may correlate with ancestry [40]. Lack of data in sources does not demonstrate absence of population differences.

9.3. Brazil and Portugal

The sources consulted contain no prevalence estimates for hereditary progressive conduction disease in Brazil or in Portugal. The available Brazilian data relate mainly to autoimmune congenital block. In the cohort of the Hospital das Clínicas of the University of São Paulo Medical School (182 anti-Ro- or anti-La-positive pregnant women, 2002–2022), 7.1% of fetuses had complete AVB. This value reflects a tertiary-centre population and not the national frequency; moreover, the institution routinely requests antibodies after a diagnosis of congenital block, so several women included had no rheumatic disease diagnosed beforehand [55]. In this cohort, 8 of the 13 newborns with block (62%) needed a pacemaker during the neonatal admission: one on the first day of life, because of a baseline rate of 30/min and signs of poor peripheral perfusion, and the others electively in the first week. The only complication after implantation was infection, in 3 newborns, which the authors present as 43% of those paced during the admission, although 3 of 8 corresponds to about 38% [55]. In inherited disease, GeneGuidance records a Brazilian family of 66 people with the PRKAG2 variant NM_016203.4:c.869A>T p.(Lys290Ile), with a high burden of pacemakers, sudden death and stroke [9]. The Brazilian book Síndromes Genéticas: Reconhecer para Tratar includes conduction block among the major criteria of Kearns-Sayre syndrome and attributes to it 20% of deaths in that syndrome [51].

For Portugal, the sources consulted contain neither epidemiological data nor clinical series of inherited conduction disease. ERN GUARD-Heart includes three full Portuguese members: Centro Hospitalar de Lisboa Ocidental, Centro Hospitalar Universitário de Lisboa Central and Centro Hospitalar de São João. It also includes Coragem, a Portuguese patient association in the network's European patient advocacy groups, and support partner Associação de Pessoas com Doenças do Miocárdio (Heart Porto) [18]. Hospital names follow the network website at access and may not reflect later administrative reorganisation. The absence of data in the sources consulted does not mean that no Portuguese or Brazilian publications exist.

9.4. European reference network and patient associations

ERN GUARD-Heart (European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart) facilitates rare and complex cardiac diagnosis and treatment access for adults and children in the European Union, bringing together 44 providers from 16 Member States [18]. Its themes include adult and childhood familial electrical diseases, familial cardiomyopathies, special electrophysiological conditions and congenital heart disease, covering this article's isolated, cardiomyopathy-associated and congenital-heart-disease-associated forms [18]. Full members span countries including Belgium, Denmark, Spain, France (including Nantes University Hospital, source of many cited French families), Italy, the Netherlands and Portugal, with associated national centres and coordination platforms elsewhere. Its website provides disease-specific patient leaflets, also in Portuguese [18]. Table 9.3 lists the network and the patient associations mentioned in the sources.

Table 9.3. European reference network and patient associations.

10. Illustrative Clinical Case

10.1. Fetal atrioventricular block with a TRPM4 variant across three generations

The main case was published in HeartRhythm Case Reports in 2025 by Holmes and colleagues and, according to the authors, is the first TRPM4 variant carrier presenting fetally; all three open-access figures were consulted for this description [52].

A healthy gravida two, para one woman receiving regular prenatal care was referred for fetal echocardiography at 32 weeks for fetal rates around 40/min and suspected AVB [52]. Previously recorded rates (129–135/min) were already below the 3rd gestational-age centile [52]. Family history showed asymptomatic RBBB and left anterior fascicular block in the fetal father, diagnosed during adolescence, and atrial fibrillation and flutter in the paternal grandmother diagnosed at 58; subsequent history identified two paternal great-uncles, one with atrial fibrillation and another supraventricular tachycardia [52]. The woman had neither recent viral infection nor rheumatological symptoms [52].

The father's baseline ECG (Figure 1A) shows sinus rhythm at 55/min, PR 157 ms, QRS 153 ms and QTc 442 ms, with RBBB, left anterior fascicular block and non-specific ST elevation attributed probably to intraventricular delay; the paternal grandmother's ECG (Figure 1B) shows sinus bradycardia at 55/min, PR 186 ms, QRS 78 ms and QTc 403 ms [52]. After variant identification, the father underwent echocardiography and Holter, normal apart from RBBB and fascicular block; the grandmother's Holter at diagnosis had confirmed atrial fibrillation and flutter [52].

Initial fetal echocardiography showed third-degree AVB with ventricular rate 43/min, cardiomegaly (cardiothoracic ratio 0.67, normal 0.50) and right ventricular dilatation, without endocardial fibroelastosis or AV valve regurgitation [52]. Because prior qualitative anti-Ro/SSA screening was positive, dexamethasone and intravenous immunoglobulin were started, with terbutaline added for chronotropic support at article-described doses, an individual suspected-immune-block decision rather than a recommendation here [52]. Presentation was unusual — late onset and absent typical anti-Ro/SSA extranodal injury — so quantitative maternal antibodies were requested: anti-Ro52 4 AU/mL and anti-Ro60 2 AU/mL, negativity threshold below 29 AU/mL; dexamethasone was stopped [52].

Over subsequent days, rhythm alternated between sustained second-degree AVB with 2:1 and 3:1 conduction and third-degree AVB [52]. Fetal Doppler (Figure 2A and 2B) documents 3:1 conduction with atrial rate 133/min and ventricular 45/min, and 2:1 conduction at 122/min and 61/min, identifying atrial contractions through mitral inflow and ventricular contractions through aortic outflow [52]. The team's predelivery protocol for fetal AVB below 50/min included testing response to intramuscular adrenaline injected through the maternal abdomen into the fetal thigh: ventricular rate rose to approximately 70/min but atrial flutter developed with atrial rate 317/min and ventricular 46/min (Figure 2C), lasting approximately 25 minutes before third-degree AVB returned [52].

At 33 weeks 1 day, severe-feature pre-eclampsia required emergency caesarean delivery [52]. The male newborn weighed 2422 g with Apgar scores 2, 5 and 6 at 1, 5 and 7 minutes; he was intubated, required repeated adrenaline doses to maintain cardiac output and was transferred to cardiac intensive care on continuous adrenaline [52]. Immediate postnatal ECG (Figure 3A) shows complete AVB with ventricular rate 65/min, and postnatal infant anti-Ro/SSA testing was negative [52].

Third-degree AVB persisted at ventricular rates 40–50/min on adrenaline; substitution with isoproterenol increased rate only transiently and, because of low output, an epicardial pacemaker with a paediatric implantable generator was placed on day 5 [52]. Shortly afterwards, rhythm unexpectedly became sinus with long PR, LBBB and intermittent atrial tachycardia runs; until discharge on day 30, it oscillated among sinus rhythm, 2:1 AV conduction and third-degree AVB [52]. The postimplant 12-lead ECG (Figure 3B) shows sinus rhythm at 133/min without ventricular pacing; the legend gives PR 188 ms, QRS 87 ms, both described as prolonged, and QTc 460 ms [52]. Article text describes LBBB in this trace whereas the legend records QRS 87 ms; both published details are reproduced without reinterpretation.

Postnatal commercial-laboratory genetic testing identified a novel heterozygous TRPM4 variant, NM_017636.4:c.3088G>A, p.(Val1030Met), classified as uncertain; nomenclature and genomic position (GRCh38, chr19:49202098 G>A) were confirmed using VariantValidator [11, 52]. Cascade testing found the same variant in the father with asymptomatic RBBB and left anterior fascicular block and grandmother with atrial fibrillation and flutter; the two great-uncles with reported arrhythmias were untested [52]. The variant has no recorded gnomAD frequency, and only one in silico model supported pathogenicity, others split between benignity and uncertainty [52].

10.2. Interpretation and lessons from the case

Authors interpret this as potentially expanding TRPM4 phenotypes to prenatal sinus bradycardia, second- and third-degree AVB and atrial arrhythmias; they note high atrial myocyte expression and that inhibition shortens action potentials in isolated atrial cardiomyocytes, making contribution to the grandmother's atrial arrhythmias plausible [52]. This is an author hypothesis supported by one case and a variant remaining uncertain [52].

The first lesson concerns immune-block differential diagnosis. The commonest fetal AVB cause is second-trimester transplacental maternal anti-Ro/SSA producing AV nodal inflammation and fibrosis, but inherited arrhythmia syndromes can also manifest as fetal AVB [52]. Three elements challenged immune block: gestational age 32 weeks when approximately 90% present before 26, absent extranodal injury such as endocardial fibroelastosis and negative maternal and infant quantitative titres despite positive qualitative screening [52]. Authors cite personal communication rather than published data that approximately 30% of qualitatively positive pregnant women have negative titres [52]. Their final recommendation — consider inherited arrhythmia syndromes with negative quantitative titres and genetically test infants with familial cascade — agrees with the French non-immune AVB cohort's proposed arrhythmia and cardiomyopathy panel in all infants and children with conduction system disease whose mothers are anti-Ro/SSA-negative [12, 52].

The second lesson concerns uncertain variants. EHRA/HRS/APHRS/LAHRS 2022 states an uncertain variant not reclassified as likely pathogenic should not guide cascade screening, which should be clinical, while robust cosegregation in several affected relatives may contribute to reclassification [10]. Here, relative testing mainly documented segregation: the variant occurred in two relatives with differing phenotypes (father's RBBB with fascicular block and grandmother's atrial arrhythmia) and retained uncertain classification in the publication [52]. Under that consensus, family surveillance continues to depend on clinical assessment rather than genotype until reclassification [10].

The third lesson is phenotypic. The father's asymptomatic RBBB and left anterior fascicular block since adolescence match classical TRPM4, where RBBB with or without fascicular block may progress to complete AVB with intrafamilial variability and incomplete penetrance [4, 9, 52]. Fetal high-grade AVB, paternal asymptomatic bundle branch block since adolescence and sixth-decade atrial arrhythmia illustrate intrafamilial variability and three-generation history value in young unexplained CCD [4, 52].

10.3. Additional case: LMNA conduction disease and genetic result timing

Inoue and colleagues at the University of Tokyo Hospital published two LMNA CCD cases in European Journal of Heart Failure in 2025 where genetic results arrived after initial implantation, necessitating further surgery; both open-access figures were consulted [83].

In the first, a 44-year-old man had atrial flutter and first-degree AVB on annual screening; his father had flutter ablated at 47 and pacemaker at 57 without familial sudden death (Figure 1A) [83]. Asymptomatic, he declined electrophysiological study and follow-up; three years later with faintness, ambulatory recording showed flutter, complete AVB and non-sustained ventricular tachycardia (Figure 1B and 1C) [83]. Echocardiography was normal and CMR showed no late enhancement; flutter underwent cavotricuspid isthmus ablation, sustained ventricular tachycardia was not induced and he was discharged with left bundle branch area pacing, paced QRS 92 ms [83]. Exome sequencing identified the pathogenic variant NM_170707.4:c.1380+1G>T in a canonical splice donor site (PVS1, PM2, PP3), Sanger-confirmed five months after surgery; laminopathy-specific 5-year sudden death risk was estimated at 52% and, eight months after implantation, a shock lead was added to convert to resynchronisation-defibrillation [11, 83]. Distant relatives declined testing; two-year follow-up showed no arrhythmic events and preserved ejection fraction [83].

In the second, a 47-year-old man without cardiovascular family history presented with exertional dyspnoea, Mobitz II second-degree AVB and non-sustained ventricular tachycardia, ejection fraction 38% without dilatation (Figure 2A–2D) [83]. Coronaries were normal, CMR showed linear intramural interventricular septal late enhancement (Figure 2E), fluorodeoxyglucose PET showed no abnormal uptake and endomyocardial biopsy was non-specific; non-dilated left ventricular cardiomyopathy with CCD without myopathy was diagnosed [83]. Urgent symptomatic CCD required treatment before results and he did not meet defibrillator criteria, so a resynchronisation pacemaker was implanted [83]. Exome sequencing subsequently identified the pathogenic canonical splice donor variant NM_170707.4:c.639+2T>C; MADIT-ICD placed him in intermediate benefit (15% 3-year malignant arrhythmia) while the laminopathy model estimated 64% at 5 years (Figure 2G), prompting conversion to resynchronisation-defibrillation 11 months after initial surgery; over two years no defibrillator therapy occurred but ejection fraction remained reduced [11, 83].

Authors emphasise that upgrade surgery exposes patients to device infection and other adverse events avoidable with timely results, panels take weeks to months and Japanese health insurance does not cover testing [83]. The case illustrates existing recommendations: in LMNA CCD requiring pacing, consider a pacing-capable defibrillator, particularly with male sex, non-sustained ventricular tachycardia, ejection fraction below 45% and non-missense variants — both were men with non-sustained ventricular tachycardia and splice variants [4, 83]. For medical genetics, the lesson is to obtain the genetic result before the first implantation whenever the clinical situation permits [83].

11. Prognosis and Long-Term Follow-Up

11.1. Natural history: what is known and unknown

Systematic longitudinal inherited CCD data are scarce, and Clinical Cardiogenetics therefore finds detailed screening and follow-up algorithms difficult, proposing individual patient and family plans [4]. Information derives from three sources with different meanings: general-population ECG-abnormality prognosis; variant-carrier cohorts usually followed and therefore treated at referral centres; and population exome studies measuring rare variant expression in individuals unselected by family history [4, 40, 41].

In the general population without known structural heart disease, unexplained sinus bradycardia below 50/min was not associated with adverse events over mean follow-up 5.4 years; in the Finnish study of 10,685 people aged 30–59 followed for 30 ± 11 years, isolated first-degree AVB (2.1%) did not increase event risk; Mobitz I without heart disease, common in athletes through vagal tone, is usually nodal and benign [4]. Mobitz II, conversely, reflects block below the AV node with high complete AVB progression, syncope and sudden death risk [4]. RBBB mortality association is disputed, with a meta-analysis showing increased risk (HR 1.17; 95% CI 1.03–1.33), and asymptomatic LBBB prognosis is age-dependent: cohorts averaging below 55 with less than 10 years' follow-up found no increased events, whereas older and longer-followed studies showed increased high-grade AVB and cardiovascular and total mortality [4]. Together these indicate good prognosis in asymptomatic young people except Mobitz II; authors question inherited CCD extrapolation because accelerated degeneration probably produces more frequent progression than in an unselected population [4].

Outside referred families, UK Biobank measured rare variant expression: among 469,511 with exomes, 25 P/LP PCCD carriers had conduction disease in 28% versus 5.3% of non-carriers (HR 6.60; 95% CI 3.14–13.8 over 6.5 million person-years), predominantly AVB (HR 23.2) and pacemaker implantation (HR 13.4); all were older than 50 at diagnosis and PR and QRS polygenic scores modestly improved prediction (C-index 0.602 to 0.618) [40]. These are not penetrance estimates for early-CCD families because the cohort comprises middle-aged adult volunteers with few carriers; absent diagnoses before 50 do not show disease cannot start earlier, as familial and paediatric cohorts demonstrate [12, 40].

Distinguishing natural history from treated disease is essential. Almost all gene-specific data below concern specialist-followed patients, many with pacemakers or defibrillators, describing prognosis under surveillance and treatment rather than untreated evolution [12, 41, 44].

11.2. Prognosis by gene and associated form

In carriers of loss-of-function SCN5A variants, the multicentre study by Tuijnenburg and colleagues included 615 probands and relatives with progressive CCD or Brugada syndrome, 111 of them symptomatic at baseline; over a median of 9.5 years (interquartile range 5.0–14.3), 41 (6.7%) had sudden death, aborted cardiac arrest, ventricular fibrillation or sustained ventricular tachycardia, corresponding to 0.7% per year, 2.0% per year in symptomatic individuals and 0.3% per year in asymptomatic individuals [41]. Initial symptoms, male sex and QRS prolongation were independent predictors, also in asymptomatic individuals in the case of sex and QRS, and asymptomatic women with a QRS below 100 ms had no events during follow-up [41]. This absence of events refers to the observed period and does not equate to a zero lifetime risk; the study is retrospective, the main outcome is arrhythmic (not progression to AVB) and, in the source consulted (abstract), the effect of implanted devices is not distinguished [41]. The 2022 consensus adds that the genotype may not stratify the risk of CCD progression, but that the hereditary aetiology has prognostic value, such as the risk of sudden death in laminopathy [10].

For TRPM4, no longitudinal full-paper cohorts were found in consulted sources; in a 2026 Italian conference abstract series of 16 carriers, 70% of 10 conduction disease patients required pacing before age 50 [42]. These preliminary incompletely reviewed data cannot estimate annual progression [42].

Cardiac laminopathy is progressive: CCD precedes dilated cardiomyopathy by median 7 years and LMNA CCD carries high malignant ventricular tachyarrhythmia risk even with preserved systolic function [4]. In the 122-carrier cohort followed for median 7 years at five centres, 59% received defibrillators for new ventricular dysfunction or AVB, 19% progressed to end-stage heart failure and 13% died; among those initially without dysfunction, 24% developed it and 7% reached end-stage failure [44]. Male sex, non-missense variants and ventricular dysfunction at initial assessment were associated with ventricular arrhythmia; ventricular dysfunction was associated with end-stage heart failure or death, while the mode of presentation had no predictive value [44]. Clinical Cardiogenetics lists male sex, non-sustained ventricular tachycardia, ejection fraction below 45% and non-missense variants as additional risk factors, and GeneReviews cites studies associating splice variants with greater sudden death risk [4, 17]. In the two additional Japanese cases with splice variants, the laminopathy model estimated 5-year risks of 52% and 64% [83].

In neuromuscular forms, pacing does not eliminate risk. In myotonic dystrophy type 1, sudden death accounts for 30% of mortality and adults retain high arrhythmic and sudden death risk despite pacemakers; non-sinus rhythm, PR ≥240 ms, QRS ≥120 ms, second- or third-degree AVB and atrial tachyarrhythmias predict sudden death [4, 49]. In autosomal dominant Emery–Dreifuss, 35% develop progressive dilated cardiomyopathy by middle age, and ventricular arrhythmias cause sudden death despite pacing, supporting defibrillators when devices are indicated [49].

11.3. Childhood non-immune atrioventricular block: treated prognosis

Mycinski and colleagues' French national cohort predominantly describes treated disease: of 385 children with isolated non-immune AVB, 286 (74.3%) received permanent pacemakers, 39 in the first year and 172 before age 10, median implant age 5 years (1.2 months for congenital AVB and 6 years for childhood AVB) [12]. Indication was prophylactic in 203 (71.0%) — predominantly mean daytime rate below 50/min after age one, ventricular pauses exceeding three RR intervals and rate below 50/min in infants — and symptomatic bradycardia in the remainder [12]. Among 263 with complete AVB at diagnosis, 35 had paroxysmal disease, of whom 33 progressed to permanent complete AVB over median 10 years; incomplete forms progressed in 84 of 122 over median 12 years [12].

After median follow-up 10 years (5–17), exceeding 10 years in 183 and 15 in 102, nobody died, developed endomyocardial fibrosis or dilated cardiomyopathy, or required biventricular pacing [12]. Treatment burden falls on pacing systems: 35 children had major complications (one tamponade, 31 lead fractures or dysfunctions and three lead endocarditis cases), and 146 of 286 paced children required at least one reintervention [12]. Among 187 epicardial systems, 86 were reoperated over median 8.7 years, 64 for generator replacement and 22 unplanned; among 95 endocardial systems, 59 were reoperated over median 13.7 years, 46 for generator replacement and 13 unplanned [12]. Some published complication percentages are inconsistent, so only absolute counts are reproduced.

Authors contrast these results with immune AVB, with high neonatal mortality and dilated cardiomyopathy risk in earlier work by the same group, and a Danish case-control study where young people paced for unexplained AVB had a 3.8-fold higher composite rate of death, heart failure admission, ventricular tachyarrhythmia or aborted sudden death [12]. They attribute discrepancy to incomplete Danish investigation, with maternal immune status and genetic testing absent in most, potentially missing prognostically important LMNA or SCN5A variants [12]. The declared limitations of the French cohort include retrospective collection over 42 years potentially underestimating adverse events and evolving genetic tests performed in only 133 (34.5%), pathogenic in 5.3% tested [12]. The favourable prognosis observed therefore applies to isolated non-immune childhood AVB investigated and treated at paediatric centres, not LMNA-, cardiomyopathy- or neuromuscular-associated forms [4, 12].

11.4. Follow-up of patients, carriers and relatives

Sources agree on three principles — complete baseline carrier assessment, periodic ECG review and urgent care after syncope — but differ on intervals, specified only in the reference text and associated-disease GeneReviews [4, 5, 10, 17]. Table 11.1 assembles consulted recommendations; intervals are expert opinion rather than trial-derived.

Table 11.1. Assessment and follow-up intervals for patients, carriers and relatives.

Two points complete Table 11.1. First, the 2022 consensus dispenses with monitoring of familial-pathogenic-variant-negative relatives, whereas the laminopathy GeneReview requests individual assessment before discharge because variants in multiple dilated cardiomyopathy genes may segregate [10, 17]. Second, with uncertain variants as in the fetal case, family screening should be clinical rather than genotype-guided [10, 52]. In the French paediatric cohort, all children with or without pacemakers had at least annual paediatric cardiology review with ECG and echocardiography; this was study protocol, not formal guidance [12].

12. Summary and Final Considerations

Cardiac conduction disease is very common in older people and almost always degenerative or secondary, but in patients younger than 50 without structural heart disease or myopathy, particularly with family history, inherited progressive disease should be suspected [2, 4, 5]. Anatomically described by Lenègre and Lev in 1964, linked to SCN5A in 1999 and TRPM4 in 2009, isolated disease predominantly involves these genes: loss of sodium channel Nav1.5 function in the former and calcium-activated cation channel gain of function in most families with the latter [4, 19–22]. The same ECG presentation may herald laminopathy, NKX2-5 or TBX5 congenital heart disease, neuromuscular disease, storage disease or mitochondrial disease, justifying the 2026 classification into isolated and associated forms [3, 10].

Diagnosis is clinical and electrocardiographic, requires secondary-cause exclusion and relies on echocardiography in all cases, tissue-characterisation imaging when pacing is indicated before age 60 and three-generation family history [4, 5, 10]. Genetic testing, recommended or considered depending on guideline, has highly population- and era-dependent yield — approximately 30% in Dutch experience to more than 50% in panel or exome series, and pathogenic variants in 5.3% of French non-immune AVB children — and guidelines differ on index-case value [4, 10, 12, 15]. Results particularly change decisions when identifying LMNA, through pacing-capable defibrillator indications, or SCN5A, through medicine avoidance and fever treatment [4, 10, 17].

No disease-modifying pharmacological treatment exists; pacemakers according to general indications are central, with laminopathy and muscular dystrophy exceptions [4]. Prognosis depends on aetiology: favourable in isolated non-immune childhood AVB treated at paediatric centres, with no deaths or cardiomyopathy over median 10 years despite half of paced children requiring reintervention; marked by approximately 0.7% annual arrhythmic events in loss-of-function SCN5A carriers; and severe in laminopathy, with 19% end-stage heart failure and 13% mortality over median 7 years in a referral cohort [12, 41, 44].

The two 2025 published cases illustrate current limitations. First, late fetal AVB with qualitatively positive but quantitatively negative anti-Ro/SSA prompted infant testing and identification of an uncertain TRPM4 variant in father and grandmother, demonstrating antibody quantification value and limitations of unclassified variants in family screening [10, 52]. Second, delayed genetic results in two LMNA patients necessitated pacemaker conversion to defibrillator through second surgery [83]. Follow-up intervals derive from expert opinion and should be family-adapted without systematic longitudinal data [4, 10].

Key points

1. Isolated PCCD is defined by unexplained progressive conduction abnormalities before age 50, structurally normal heart and no skeletal myopathy, particularly with family history; SCN5A and TRPM4 are principal isolated genes and LMNA the heart-failure-associated gene [2, 5].
2. Fetal or infant AVB is overwhelmingly immune-mediated; negative quantitative anti-Ro/SSA should prompt inherited channelopathy consideration and genetic testing with familial cascade [12, 52].
3. Family history should span three generations and seek CCD, sudden death, arrhythmias, pacemakers or defibrillators, cardiomyopathy, transplantation, congenital heart disease and neuromuscular disease, interpreted by relative age [4].
4. The 2022 consensus recommends four core genes (SCN5A, LMNA, GLA and PRKAG2); Clinical Cardiogenetics guides selection by associated phenotype; yield varies greatly between series [4, 10].
5. Uncertain variants should not guide cascade screening; family screening should then be clinical [10].
6. With pacing-requiring CCD and an LMNA variant, consider a pacing-capable defibrillator, particularly with male sex, non-sustained ventricular tachycardia, ejection fraction below 45% or non-missense variants; obtaining results before initial implantation avoids second surgery [4, 83].
7. In loss-of-function SCN5A carriers, initial symptoms, male sex and prolonged QRS predict arrhythmic events; avoid sodium channel blockers and promptly treat fever [4, 10, 41].
8. In myotonic dystrophy type 1 and autosomal dominant Emery–Dreifuss, pacemakers do not eliminate sudden death risk [4, 49].
9. Isolated non-immune childhood AVB has favourable treated prognosis, with no deaths or dilated cardiomyopathy over median 10 years in the French cohort but frequent pacing-system reintervention [12].
10. P/LP carriers should receive symptom and ECG reassessment every 1–3 years, and LMNA carriers echocardiography every 1–2 years or at least annually with any ECG abnormality; any syncope requires urgent assessment [4, 17].
11. In UK Biobank, unselected by family history, 28% of 25 P/LP PCCD carriers had conduction disease, all diagnosed after age 50; genotype requires clinical and family context [40].

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