Familial Dilated Cardiomyopathy

Nonsyndromic genetic dilated cardiomyopathy — TTN, LMNA, MYH7, BAG3, FLNC, RBM20, DSP, PLN and other genes; syndromic, neuromuscular and arrhythmogenic forms considered in the differential diagnosis.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Dilated cardiomyopathy (DCM) is myocardial disease defined by LV dilatation with systolic dysfunction after exclusion of common clinically detectable causes, particularly coronary disease, valve disease and loading conditions. It may remain asymptomatic for years and present with heart failure, arrhythmia, mural thrombus embolism or sudden death; even treated, it carries substantial mortality and is the most frequent heart transplant indication [1]. “Familial” denotes no single molecular entity: it encompasses dozens of genes with distinct mechanisms whose expression depends on age, sex and environmental factors. Genetics has two clinical purposes: guiding prognosis and treatment decisions, and identifying at-risk relatives before irreversible injury [5].

Goodwin and Oakley's first cardiomyopathy classification (1972) and the World Health Organization definition (1980) described DCM as myocardial disease of unknown origin with systolic dysfunction and LV dilatation. The American Heart Association adopted a chamber enlargement and systolic dysfunction definition with normal wall thickness in 2006, while the European Society of Cardiology (ESC) restricted the concept in 2008 to dysfunction and dilatation unexplained by loading or sufficient coronary disease [1]. In 2016, the ESC working group proposed a spectrum including preclinical phases such as isolated familial dilatation, introducing hypokinetic non-dilated cardiomyopathy (HNDC), global systolic dysfunction without dilatation [1, 16]. ESC 2023 replaced this with non-dilated left ventricular cardiomyopathy (NDLVC), defined by non-ischaemic LV scar or fatty replacement irrespective of contractility, or isolated global hypokinesia without scar [4].

Familial recognition has a methodological milestone in Michels and colleagues (1992): among 59 idiopathic DCM patients, systematic assessment of 315 relatives identified familial disease in 12 index patients (20.3%) and ventricular dilatation with normal ejection fraction in 9.2% of healthy relatives versus 1.8% of controls—early evidence that history underestimates familial disease and partial phenotypes exist [17]. In 1999, the European collaborative group published familial DCM study criteria still used in cardiogenetics [18, 19], and Fatkin and colleagues described five missense LMNA variants in families with DCM and conduction disease, showing a nuclear envelope protein could cause isolated cardiomyopathy [20]. Identification in 2012 of truncating TTN variants in approximately 25% of familial and 18% of sporadic forms transformed test yield, possible only after widespread next-generation sequencing because of gene size [19, 21].

The genetic architecture of DCM is the most heterogeneous of the cardiomyopathies: more than 50 genes have claimed associations, but only a fraction have robust evidence, and the systematic review by the Clinical Genome Resource (ClinGen) classified 19 genes as having high evidence in 2021, a number that rose to 35 high-evidence curations in the reassessment published in September 2026 [1, 9, 10]. In parallel, studies of American cohorts showed that, if all living first-degree relatives were screened, about 30% of patients with idiopathic DCM would have familial disease [22]. This article covers non-syndromic familial DCM; syndromic, neuromuscular and metabolic forms and arrhythmogenic cardiomyopathy are presented as differential diagnoses. Hypertrophic cardiomyopathy shares sarcomeric genes, but the variant mechanisms and therapeutic approach are distinct.

2. Molecular Genetics and Pathophysiology

2.1. Genetic architecture and disease models

Unlike hypertrophic cardiomyopathy (sarcomere) and arrhythmogenic RV cardiomyopathy (desmosome), DCM genes encode diverse structures and pathways: sarcomere and Z disc, cytoskeleton, nuclear envelope, splicing regulation, ion channels, sarcoplasmic reticulum, extracellular matrix, desmosome and mitochondrion [1, 2]. Figure 5.1 in Cowan, van Spaendonck-Zwarts and Hershberger depicts these locations: ryanodine and phospholamban in intracellular calcium regulation; actin, myosin-binding protein C, heavy and light myosin chains, tropomyosin, troponins and titin in the sarcomere; desmin and desmosomal proteins in force transmission; lamins A/C and thymopoietin in the nucleus; laminin α4 and the dystrophin–glycoprotein complex connecting to the matrix [1].

Inheritance is usually autosomal dominant, with incomplete age-dependent penetrance and variable expressivity: one familial carrier may develop structural cardiomyopathy and another only conduction disease or arrhythmia [1]. A proposed multihit threshold model combines high-effect rare variants, moderate- or small-effect variants and environmental factors including sex, blood pressure, activity, toxins, pregnancy and puerperium [1, 5]. More than one relevant rare variant was found in up to one-third of one cohort and approximately one-quarter of LMNA families in another; among 19 LMNA pedigrees, six had affected relatives lacking the familial variant, and in five those relatives had pathogenic variants in other genes [1]. Polygenic scores are associated with DCM risk but remain clinically inapplicable [5]. Approximately 6% of DCM patients have combined genetic and non-genetic aetiology, precluding dismissal of genetic testing because of an acquired cause [5].

Missense variants predominate, but in-frame insertions/deletions, frameshift, splice and nonsense variants occur; recessive, X-linked and mitochondrial inheritance is also described [1]. The Oxford Desk Reference estimated recessive inheritance in approximately 15% of affected families and gave overall age-dependent penetrance of 10% before 20 years, 34% at 20–30, 60% at 30–40 and 90% after 40, referring to its conduction disease and X-linked categories and predating expanded sequencing [8]. These historical estimates do not replace gene-specific penetrance below.

2.2. High-evidence genes and relative contribution

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; AV, atrioventricular; CMT, Charcot-Marie-Tooth; HMERF, hereditary myopathy with early respiratory failure; LGMD, limb-girdle muscular dystrophy. Table sources: fractions and allelic disorders from GeneReviews (preliminary estimates based on at least two large series studies) and Table 5.2 of the cardiogenetics book; 2021 ClinGen classification; transcripts checked against version 1.5 of the MANE set (Matched Annotation from NCBI and EMBL-EBI) [1, 2, 9, 23]. Table 5.2 of the book, built from genes present in at least three commercial panels in 2018, also includes ABCC9, ALMS1, CAV3, CRYAB, CSRP3, DMD, DOLK, EYA4, FKRP, FKTN, GATAD1, ILK, LAMA4, LAMP2, LDB3, LRRC10, MYH6, MYPN, NEBL, NKX2-5, PDLIM3, PRDM16, RAF1, SDHA, SGCD, TAZ, TBX20, TCAP, TMEM43, TMPO, TXNRD2, desmosomal genes and others, many with limited evidence for isolated DCM [1]. The association of ABCC9 with isolated DCM now has limited or disputed evidence, and gain-of-function variants in this gene cause Cantú syndrome, with high-output cardiac hypertrophy. The 2026 ESC clinical consensus recommends a core panel with the 19 high-evidence genes and adds DMD, based on the European Molecular Genetics Quality Network recommendation for isolated X-linked DCM [5].

The 2024–2025 ClinGen re-evaluation published in September 2026 assessed 68 genes and 72 gene–disease–inheritance relationships: 35 curations had high evidence (16 definitive, 10 strong, 9 moderate), nine new genes reached this category (BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, RPL3L), twelve had high evidence for recessive inheritance, and PLEKHM2, PRDM16, TBX20 and TNNI3K rose from low to high evidence; JPH2 was split into dominant (strong) and recessive (limited), LDB3 strong recessive and limited dominant, TNNI3 strong in both, and MYBPC3 limited in both [10]. The 2021 core panel is therefore a minimum rather than a closed list, especially with consanguinity or paediatric onset.

2.3. TTN and the length dependence of truncating variants

Titin spans the Z disc to the M line, covering half a sarcomere; its elastic I-band segment determines passive tension and the A-band segment acts as a molecular ruler [7]. Truncating TTN variants (TTNtv) are the most frequent familial DCM genetic cause but also occur in controls: the foundational study found them in 27% of next-generation-sequenced DCM patients versus 1% of hypertrophic cardiomyopathy patients and 3% of controls, with cosegregation (combined lod 11.1), observed penetrance above 95% after 40 and earlier male adverse events [21]. With multiple isoforms, two cardiac-specific, truncation in an exon excluded from cardiac isoforms may have no effect; filtering to cardiac-included exons markedly reduces control variants while retaining patient prevalence up to 22% [1]. Roberts and colleagues combined sequencing of 5267 individuals with myocardial RNA and protein analysis, defining relative exon inclusion and supporting a mechanism dependent on residual protein length [24].

DCM-associated TTNtv concentrate in the A band and were absent from Z-disc and M-band regions in the foundational study [21]. An international registry published July 2026 with 467 phenotypically affected carriers (81% probands, 73% male, median age 47) found 80% A-band, 15% Z-disc/I-band and 5% M-band variants; all regions were enriched relative to gnomAD, with greater estimated A-band penetrance, while sudden death or major ventricular arrhythmia occurred in 45% of M-band, 23% of Z/I and 12% of A-band carriers (p = 0.001), often initially. Location was independently predictive, while ejection fraction predicted only in A and Z/I groups [25]. TTN missense variants, averaging 23 per person in the book and approximately one rare variant per unaffected individual in the Exome Sequencing Project, are not clinically associated with disease [1, 2, 8].

TTNtv often predispose through additional factors. DCM TTNtv carriers drinking above recommended levels had an absolute 8.7% lower LV ejection fraction (LVEF) than non-carriers without excessive consumption, and DCM gene variants were more frequent in alcoholic cardiomyopathy than controls (13.5% versus 2.9%) [26]. In cancer therapy-induced cardiomyopathy, TTNtv occurred in 7.5% versus 0.6–1.1% of comparison populations, with more heart failure, atrial fibrillation and poorer recovery [27]. In peripartum cardiomyopathy, 15% of women had truncating DCM gene variants (TTN in 10% versus 1.4% of the reference population), resembling idiopathic DCM distribution [28].

2.4. LMNA and laminopathies

LMNA (1q22) encodes lamins A and C through alternative splicing, nuclear lamina intermediate filaments supporting the envelope, binding chromatin and participating in DNA repair [6, 7]. Two non-exclusive injury hypotheses are nuclear fragility under repeated mechanical stress with apoptosis, and disruption of lamina-associated chromatin–protein complexes with altered gene expression; mitogen-activated kinase pathways, particularly p38, are activated in LMNA DCM [6, 7]. The mechanism is loss of function through splice, indel, truncating and missense variants [6]. Laminopathies include muscular forms (dominant/recessive Emery–Dreifuss, LGMD 1B, congenital muscular dystrophy), Dunnigan familial partial lipodystrophy (mostly arginine 482 variants), recessive CMT2B1, Slovenian-type heart–hand syndrome and Hutchinson–Gilford progeria, the last caused by synonymous NM_170707.4:c.1824C>T p.(Gly608=), activating cryptic splicing and producing progerin, a toxic gain-of-function mechanism unrelated to DCM [6, 7, 29]. GeneGuidance's LMNA-associated 0.3/100,000 frequency refers to Emery–Dreifuss of all genes rather than LMNA DCM, which has no validated population estimate [7].

The French PNDS on laminopathies with cardiac presentation, which is limited to adult-onset forms and excludes infantile forms because they are distinct nosological entities, adds structural and molecular details. The gene has 12 exons and spans about 24 kb and, through alternative splicing, produces four A-type isoforms (A, AΔ10, C and C2), of which lamins A and C are the main ones; these share the first 566 amino acids, differ in the C-terminal domain and are absent in early embryonic stages. The document places the locus at 1q21.2–q21.3, an older localisation than the 1q22 band adopted in current databases [6, 15]. A total of 623 variants associated with more than 15 phenotypes had been described (UMD-LMNA and HGMD databases), with increasing overlap between phenotypes, suggesting a continuum. Among the first 301 variants published, 72% were missense, 9% in-frame insertions/deletions, 9% frameshift insertions/deletions, 7% canonical splice-site variants and 5% nonsense. Variants affecting tissues other than striated muscle cluster in specific residues or exons, whereas variants associated with striated muscle (68% missense) are distributed throughout the gene, with no hotspots for cardiac or skeletal forms. The three entities — Emery–Dreifuss, DCM with conduction disease and limb-girdle dystrophy 1B — can coexist in the same family. In the UMD-LMNA database, 33% of patients with isolated cardiac disease had potentially truncating variants, versus 8% of patients with combined cardiac and skeletal involvement [15]. Histologically, cardiac laminopathy is characterised by dysmorphic nuclei with nuclear envelope dehiscence and diffuse myocardial fibrosis. Fibrofatty degeneration of the atrioventricular junction, subsarcolemmal glycogen deposits or fibrofatty infiltration resembling arrhythmogenic right ventricular dysplasia are sometimes found. In a murine model, cardiomyocyte maturation was already altered prenatally, with early epigenetic changes. The PNDS also notes that common LMNA variants of modest effect have been implicated in multifactorial DCM, that LMNA loss of function has been described as a primary cause of kidney disease and that some rare extracardiac forms, such as mandibuloacral dysplasia with lipodystrophy, have recessive inheritance [15].

2.5. Other genes with distinctive phenotypes

BAG3 encodes a cochaperone linking HSP70 to small heat-shock proteins at the Z disc; failure prevents removal of damaged sarcomeric proteins, disorganising myofibrils and relocating protein to the Z disc [7]. In the largest series, 129 European carriers, DCM was present in 57.4% initially and 68.4% after median 38 months; 26.1% of initially phenotype-negative carriers developed DCM, penetrance above 40 was 80%, and DCM adverse events occurred at 5.1% annually [30]. Recurrent NM_004281.4:c.626C>T p.(Pro209Leu) causes severe childhood-onset myofibrillar myopathy with adolescent cardiomyopathy and respiratory failure, distinct from adult loss-of-function DCM [7, 29].

FLNC encodes actin-binding filamin C in Z and intercalated discs; truncating variants cause haploinsufficiency (ClinGen-confirmed dosage) and DCM/arrhythmogenic cardiomyopathy with extensive fibrosis and ventricular arrhythmias, whereas missense variants more often produce hypertrophic, restrictive and myopathic phenotypes [7, 31]. RBM20 regulates TTN and other target splicing through intronic UCUU binding; loss prevents titin isoform transition and increases sarcomeric compliance [7]. Pathogenic variants cluster in exon 9, such as NM_001134363.3:c.1906C>T p.(Arg636Cys) and c.1907G>A p.(Arg636His); GeneReviews regards DCM causality outside this hotspot as uncertain [2, 29].

DSP encodes desmoplakin, a force transducer between desmosomes and intermediate filaments; in 107 patients with pathogenic variants compared with 81 PKP2 carriers, left-predominant cardiomyopathy was exclusive to DSP (55% versus 0%), subepicardial LV late gadolinium enhancement was present in 40% of those studied by MRI and, in 35% of these, with normal LVEF; episodes of acute myocardial injury with chest pain and elevated troponin occurred in 15% [32]. PLN encodes phospholamban, which inhibits SERCA2a in diastole; the Dutch founder variant NM_002667.5:c.40_42del p.(Arg14del), historically described as c.40_42delAGA, causes DCM and arrhythmogenic cardiomyopathy in the same families, with low ECG voltage as a hallmark [19, 29, 33]. DES encodes desmin; in an individual-patient-data meta-analysis of 230 patients, the cardiac phenotype was heterogeneous (dilated 14.8%, restrictive 13.5%, arrhythmogenic 7.0%), and the most frequent major event was conduction disease (41.7%), ahead of heart failure (18.7%) and sustained ventricular arrhythmia (15.7%), with familial penetrance of 63.6% [7].

Sarcomeric genes shared with hypertrophic cardiomyopathy (MYH7, TNNT2, TNNC1, TPM1, ACTC1) cause DCM through molecularly distinct variants, for example altered calcium sensitivity [19]. SCN5A associates DCM with conduction disease and atrial/ventricular arrhythmias across a spectrum including Brugada and long QT type 3 [7, 34]. In DMD, mutations affecting cardiac dystrophin expression more than skeletal muscle—at the exon 1 exon–intron boundary, nonsense exon 29, intron 11 rearrangements or central-domain deletions—cause X-linked DCM with absent or mild weakness [35].

3. Clinical Spectrum and Manifestations by System

3.1. Presentation and natural history

DCM usually manifests from the fourth decade but can arise at any age including fetally; the reference chapter citing the European cardiomyopathy pilot registry gives heart failure presentation in 80–85%, arrhythmia in 15% and thromboembolism in 1–2%, with some diagnosed only at sudden death autopsy [1, 2]. Heart failure produces congestion (oedema, orthopnoea, paroxysmal nocturnal dyspnoea) and low-output symptoms (fatigue, exertional dyspnoea); arrhythmias and conduction disease usually accompany advanced disease, except genes producing arrhythmia disproportionate to ventricular dysfunction (DES, FLNC, LMNA, SCN5A) [2]. Peripartum cardiomyopathy, formerly separate, is now considered part of the DCM spectrum [2].

Treatment changed natural history: before modern therapy, reported mortality was 66% within two years; with current medicines and devices, book-cited Italian and Japanese cohorts give 20% at five and 35% at ten years [1]. These describe diagnosed, treated centre-based patients, not asymptomatic carriers. Genetic aetiology alters prognosis: among 1005 genotyped Spanish probands, major cardiovascular composite events occurred in 31.7% genotype-positive versus 19.8% genotype-negative patients (hazard ratio [HR] 1.51; 95% confidence interval [95% CI] 1.17–1.94), with more end-stage failure (16.1% versus 8.7%) and malignant ventricular arrhythmia (19.6% versus 12.2%), and less reverse remodelling (39.6% versus 46.2%), differing by gene [36].

3.2. Gene-specific differences

SHaRe means Sarcomeric Human Cardiomyopathy Registry; abbreviations are AF (atrial fibrillation), VT (ventricular tachycardia), VF (ventricular fibrillation) and NSVT (non-sustained ventricular tachycardia).

SHaRe, published in 2026, analysed 3410 DCM/arrhythmogenic cardiomyopathy patients and genotype-positive relatives: male predominance 61%, TTNtv less frequent in women (odds ratio [OR] 0.42), while DSP (OR 3.3) and non-TTN sarcomeric variants (OR 1.68) were more frequent in women; among 174 diagnosed before 18, age distribution was bimodal with infantile and adolescent peaks, predominantly non-TTN sarcomeric variants [37]. Among 3117 genotyped DCM patients in the same registry, cumulative AF prevalence was 23.6%; LMNA was the sole independently associated incident AF genotype (HR 5.52), and AF predicted more composite heart failure, ventricular arrhythmia and death events (HR 1.58) [38].

3.3. LMNA: typical temporal sequence

LMNA cardiomyopathy usually starts with sinus and AV node disease—sinus bradycardia, low-voltage P waves, first-degree atrioventricular block (AVB) with initially normal QRS—accompanied early by atrial premature beats, atrial tachycardia/AF and ventricular premature beats/VT; progression brings complete AVB, malignant ventricular arrhythmia or sudden death, then DCM with failure or embolism [6, 34]. Among 64 carriers, median time from ECG abnormalities to LV dysfunction was seven years; among 122 followed for median seven years, AVB prevalence rose from 46% to 57%, atrial arrhythmia from 39% to 63%, ventricular arrhythmia from 16% to 34% and LV dysfunction from 44% to 57%; 59% received ICDs, 19% developed end-stage failure and 13% died [39, 42]. Among those without ventricular dysfunction at presentation, 24% developed new dysfunction and 7% end-stage failure [42]. Dilatation may be mild despite progressive disease, and some have skeletal weakness with elevated creatine kinase (CK) [6].

The French PNDS brings together the series that define the natural history of adult cardiac laminopathy [15]. Onset occurs mainly between 25 and 45 years of age, but may occur in adolescence or only at 50–60 years. Expression is slightly earlier in men and variable within the same family, and absence of disease in an adult carrier is very rare. Overall penetrance of cardiac involvement was 57–64% in published series and 88–100% above 35 years of age. Rhythm manifestations precede the cardiomyopathy by about ten years on average, and supraventricular arrhythmias affected 73% in one series. The figures from the main cohorts, all of patients followed at specialist centres, are as follows:

Sources: studies as summarised in the PNDS [15, 20, 42–44].

The typical electrocardiogram shows low-amplitude P waves, a long PR interval and normal QRS duration. Myocardial fibrosis is early and is detected on histology and CMR even in asymptomatic carriers with a normal echocardiogram; septal fibrosis is associated with a long PR interval and ventricular arrhythmias and may explain septal hypokinesia, AV block and arrhythmia. Ventricular arrhythmia or appropriate ICD therapy may precede LV dysfunction and, sometimes, conduction disease itself. In a cohort compared with idiopathic DCM, LMNA carriers had an independent, approximately fivefold higher risk of arterial and venous thromboembolism. The life-threatening complications are, in order, ventricular arrhythmias (and, to a lesser extent, high-grade block), HF with reduced ejection fraction and stroke, almost always due to atrial arrhythmia [15].

Beyond the typical form, the PNDS describes less frequent cardiac phenotypes. Some patients have hypokinetic non-dilated cardiomyopathy, with reduced LVEF without dilatation. LMNA variants were found in about 5% of left ventricular noncompaction cases and in about 4% of definite or probable arrhythmogenic right ventricular dysplasia cases, the latter usually with conduction disease. LV apical aneurysm with ventricular arrhythmia without initial dilatation or dysfunction and isolated LV apical hypoplasia have also been described. Atrial dilatation sometimes predominates over ventricular dilatation. Cardiac expression in children is very rare: it occurs in congenital muscular dystrophies or early forms of Emery–Dreifuss, and in a series of three children the first manifestation was atrial arrhythmia, followed by HF with diarrhoea and oedema and a rapid fall in LVEF [15].

3.4. Extracardiac manifestations

Isolated DCM has no systemic involvement by definition, but allelic genes may show extracardiac signs: weakness or raised CK (LMNA, DES, FLNC, BAG3, TTN, DMD), joint contractures (Emery–Dreifuss), lipodystrophy (LMNA), woolly hair and palmoplantar keratoderma (DSP), sensorineural loss (EYA4, mitochondrial disorders) [2, 5, 6, 8]. Systemic and pulmonary thromboembolism are recognised complications of intracavitary thrombus or AF [8]. Neuromuscular cardiac involvement may include impulse formation/conduction defects, dilated, hypertrophic, noncompacted or restrictive cardiomyopathy, secondary valve insufficiency or intracavitary thrombus [35].

4. Clinical Recognition and Warning Signs

The starting point is suspected genetic aetiology in apparently idiopathic DCM—even with an identified acquired factor. Family history should span at least three generations, seeking heart failure, cardiomyopathy, transplantation, sudden death (particularly before 40, including single-vehicle accidents, drownings and sudden infant death), pacemaker or ICD, young-age stroke, muscle disease and hearing loss [1, 8, 12]. Because history is insensitive, first-degree clinical evaluation is recommended in every case, even with negative history [1].

When the suspicion of familial DCM arises from a sudden death, the circumstances of the death guide the hypothesis. The French PNDS on sudden death in the young (2022) defines unexplained sudden death as an unexpected death without an evident cause after the first year of life, occurring within one hour of the change in cardiovascular status when witnessed or, when unwitnessed, in an individual seen alive and well in the preceding 24 hours; below one year of age, sudden infant death mostly has other causes [13]. In hypertrophic cardiomyopathy sudden death occurs mainly at rest, whereas exertional sudden death in a young person should raise the possibility of arrhythmogenic cardiomyopathy with left-sided involvement, including forms related to LMNA, FLNC or DSP, which gives echocardiography and CMR a central place in the investigation. The document adds clues to look for: episodes classified as epilepsy during life that may have been arrhythmias, road traffic accidents without an apparent cause, drowning of a good swimmer and a diagnosis of aneurysm rupture communicated to the family without autopsy, frequently attributed without grounds and acceptable only after post-mortem examination; the differential includes non-cardiac causes such as stroke and aneurysm rupture [13].

The Madrid DCM Genotype Score, developed in 1015 Spanish patients and validated in 1097 Maastricht/Trieste patients, uses five variables—familial DCM (OR 2.29), low limb-lead voltage (OR 3.61), skeletal myopathy (OR 3.42), no hypertension (OR 2.28) and no left bundle branch block (OR 3.58)—estimating positivity from 3% without predictors to 79% with four or more (C-statistic 0.74 in both cohorts) [45]. ESC 2026 proposes it mainly for resource-limited testing prioritisation and adds high initial arrhythmic burden as a genetic clue [5].

Beyond cardiovascular examination, assess muscle bulk and strength (Becker calf hypertrophy, Gowers manoeuvre, arm elevation), elbow and ankle contractures, and paediatric dysmorphic/syndromic signs [1, 8]. Patient-accessible tools may advance diagnosis: smartwatch bradycardia alerts led to LMNA cardiomyopathy diagnosis in an asymptomatic 47-year-old man in section 10's published case [46].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

Normal LVEF's lower limit was traditionally 50%; population studies give 52% as the adult two-standard-deviation limit, while heart failure guidelines treat 40–49% as intermediate [1]. LV size assessment evolved from M-mode equations derived in 229 individuals to height-/sex-adjusted standards in 1099 adults and current sex-/body-surface approaches; growth requires specialist paediatric assessment [1, 2]. Less strict relative criteria detect partial phenotypes: dilatation with normal function, low LVEF without dilatation, or normal echo with significant ECG conduction/arrhythmia abnormalities [1, 2].

5.2. Aetiological and imaging evaluation

The diagnostic process includes a history targeted at known causes and exposures (chemotherapy, alcohol, drugs, occupational exposures), physical examination, electrocardiogram (ECG), blood tests for endocrine dysfunction, infection, metabolic abnormalities and nutritional deficiencies, exclusion of ischaemia — coronary angiography is the reference standard, particularly in men above 40 and women above 45 years of age or with risk factors — and cardiac imaging [1]. Echocardiography characterises dimensions and function and suggests causes (valve disease, ischaemic regional wall motion abnormalities, thick septum of infiltrative disease); CMR quantifies more accurately and characterises tissue, distinguishing ischaemic scar, myocarditis, amyloidosis, sarcoidosis and the fibrofatty replacement of arrhythmogenic cardiomyopathy with left-sided involvement [1]. The Oxford Desk Reference proposes as baseline investigation an echocardiogram, 12-lead ECG with rhythm strip, 24-hour Holter, total CK and MB isoenzyme and CMR [8]. For suspected laminopathy, the French PNDS defines the initial cardiac and extracardiac assessment, coordinated by a reference or competence centre [15]. The ECG looks for AV block (with PR measurement), bundle branch block, particularly complete left bundle branch block, loss of anterior R waves and ectopic beats. Echocardiography assesses LVEF (<50%), global strain and dilatation, which is often mild or absent. CMR looks for late gadolinium enhancement, frequently septal, and early changes not visible on echocardiography. Holter monitoring looks for conduction disease, atrial arrhythmia and runs of NSVT. Exercise testing, preferably with oxygen uptake measurement, assesses functional capacity and exercise-induced arrhythmias. Haemodynamic catheterisation is reserved for discussion of mechanical support or transplantation. Blood tests include natriuretic peptides, CK, iron studies in HF, lipid profile and blood glucose; in a cohort of 53 patients, elevated troponin and natriuretic peptides were associated with ventricular arrhythmia [15].

The same document indicates a systematic extracardiac assessment in all LMNA variant carriers, intended to guide referral to other specialties [15]:

ESC 2022 recommends considering late-enhancement CMR in DCM/HNDC for aetiology and ventricular arrhythmia/sudden death risk (IIa, B) [48]. ESC 2023 cardiomyopathy guidelines, read in full, recommend contrast CMR initially in all cardiomyopathies (I, B); consider it during follow-up for progression/risk (IIa, C), with text proposing 2–5-year intervals by baseline severity and course; consider it in genotype-positive/phenotype-negative relatives with an identified familial causal variant for diagnosis/early disease (IIa, B), and possibly in phenotype-negative relatives without a genetic diagnosis (IIb, C) [4]. NDLVC ambulatory ECG monitoring is recommended annually or with clinical change (I, C) [4]. Dutch endorsement adapts CMR/Holter intervals locally [14]. The DCM text also advises considering CMR in normal-function carriers of higher sudden death risk variants (e.g. FLNC, DES, DSP, PLN, LMNA, TMEM43, RBM20) [4]. A 2026 study of 925 patients across 22 European centres found conduction “corridors” within late enhancement (17.3%) and high-risk genotypes (12.9%) independently associated with major ventricular arrhythmia (subdistribution HR 1.25 per corridor and 2.28 for genotype); an algorithm combining enhancement, ≥4 corridors and genotype had five-year AUC 0.72 versus 0.57 for LVEF ≤35% [49]. This observational study lacks prospective intervention validation.

5.3. Genetic testing: indications, strategies and limitations

The US Heart Failure Society of America and American College of Medical Genetics and Genomics (HFSA/ACMG, 2018) guidelines recommend genetic testing in all patients with idiopathic DCM, familial or sporadic, regardless of age, with pre- and post-test counselling and referral of infants and children to centres with experience in syndromic forms [1, 12, 50]. The 2023 ESC guidelines recommend genetic testing in patients fulfilling diagnostic criteria for cardiomyopathy when it enables diagnosis, prognostication, therapeutic stratification or reproductive decision-making, or when it enables cascade evaluation of relatives who would otherwise remain under prolonged surveillance (class I, level B); they also recommend testing a deceased individual with cardiomyopathy identified at autopsy if a genetic diagnosis would facilitate the management of relatives (I, C), allow testing when it brings net benefit to the patient even without these purposes (IIb, C) and, in the borderline phenotype that does not fulfil criteria, only after detailed assessment by a specialised team (IIb, C) [4]. Genetic counselling by a trained professional is recommended for families with inherited or suspected inherited cardiomyopathy, regardless of whether testing is performed (I, B), as are pre- and post-test counselling in all those tested (I, B) and testing with access to a multidisciplinary team with expertise in variant interpretation (I, B) [4]. The text of the DCM section reports causal variants in up to 40% of patients in contemporary cohorts, in more than 20% of non-familial cases and in 10–15% of forms associated with chemotherapy, alcohol or the peripartum period, considers testing beneficial in all patients with DCM, including children and these acquired forms, states that age should not limit the indication and allows, where resources are limited, prioritisation scores such as the Madrid DCM Genotype Score [4]. The 2022 ESC guidelines on ventricular arrhythmias frame the indication differently: genetic testing including at least LMNA, PLN, RBM20 and FLNC is recommended in DCM/HNDC with AV conduction delay before 50 years of age or with a family history of DCM/HNDC or of sudden death in a first-degree relative before 50 years of age (I, B), and should be considered for risk stratification in apparently sporadic DCM/HNDC of young onset or with signs of an inherited aetiology (IIa, C) [48]. The 2021 ESC heart failure guidelines, in the table dedicated to DCM/HNDC, indicate genetic counselling and testing in all patients with DCM or HNDC and in adult first-degree relatives when a defined causal variant is present, without assigning a class of recommendation to this statement [51]. The 2022 EHRA/HRS/APHRS/LAHRS consensus recommends testing in probands with DCM and a family history, with a first line of definitive- or strong-evidence genes (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN, DSP), and in DCM with a history of premature sudden death or suggestive signs (AV block, sinus node dysfunction, elevated CK); it considers testing useful in apparently sporadic DCM, particularly with LVEF <35%, a malignant arrhythmic phenotype or young age, and possibly worth considering in peripartum or alcoholic forms; it recommends predictive testing in children from 10–12 years of age, to be considered below that age particularly when there is early-onset disease in the family [52]. GeneReviews extends the indication to peripartum cardiomyopathy [2]. The French PNDS considers that suspected laminopathy mandates testing and that only the identification of an ACMG class 4 or 5 variant confirms the diagnosis [15]. Sequencing of the coding regions and intron–exon junctions is performed by gene-targeted Sanger sequencing, when clinical suspicion is strong, or by a next-generation panel, usually of 40 to 80 genes, in the investigation of DCM, conduction disease, arrhythmia or extracardiac signs. Post-mortem testing after sudden death or acute HF is ideally performed on fresh frozen tissue, particularly spleen or liver, and remains of value for relatives even when the autopsy already suggests cardiomyopathy. Variants that create or abolish splice sites outside the canonical sites are often classified as VUS; prediction tools and minigene assays can reclassify them, which does not apply to missense VUS without a dedicated functional test. A variant already described in other laminopathy phenotypes mandates a search for the corresponding metabolic, muscular or progeroid involvement [15]. In the following table, P/LP denotes pathogenic or likely pathogenic variants and VUS variants of uncertain significance.

Without dysmorphism, myopathy, intellectual disability, young-onset diabetes, hearing loss or paediatric onset, a core gene panel is preferred; expanded panels mainly add VUSs without materially increasing causal variants [5]. Exome/genome is preferred in infantile DCM to cover more genes, detect de novo variants and identify unexpected disease; introduction reduced unexplained paediatric DCM from two-thirds to approximately 50% [1]. Reanalysis or repeat testing increases yield after an initial negative result [2, 5].

Technical limits must be explicit. Sequencing detects point variants and small indels but usually not exon deletions/duplications; in LMNA, more than 99% of known pathogenic variants are sequenced and fewer than 1% detected by deletion/duplication analysis, with at least three deletion-associated DCM reports; typical laminopathy with negative sequencing warrants MLPA (multiplex ligation-dependent probe amplification) or equivalent [6, 34]. Single-gene LMNA testing is rarely useful; combined cardiomyopathy/arrhythmia panels are preferred with predominant arrhythmia and minimal DCM [6]. DSP deletions/duplications require copy-number analysis [7]. TTN truncation requires checking inclusion in cardiac isoform exons [7, 24]. Detectable variant proportion is not clinical sensitivity: even in familial DCM, more than half of families lack an actionable result [1].

Reports should state gene, versioned reference transcript (MANE Select transcripts in 2.2), cDNA/protein HGVS, zygosity, five-class American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) classification and limitations [1, 23]. VUSs neither establish nor exclude diagnosis and should not support predictive testing; affected-relative segregation is investigational for reclassification, and most families are too small [1, 5, 6]. The book treats variants in unestablished genes as uncertain until proven otherwise [1]. Classification may change, requiring updated databases such as ClinVar and periodic reclassification [1].

After a sudden death, the genetic diagnosis depends on the autopsy and on appropriate sampling. The French PNDS on sudden death in the young recommends a complete autopsy, forensic or scientific, by a team experienced in cardiac pathology, with examination of all organs according to a systematic method and a standardised report [13]. When a cardiac cause is suspected, the whole heart is sent to a cardiac pathologist, after external examination, transverse sections of the coronary arteries and, at most, one short-axis section near the apex; histology includes at least 7 to 10 systematic blocks (right ventricle, left ventricle, septum, coronary arteries), in addition to those guided by lesions, and radiography, photography and, where available, post-mortem CT and MRI complete the examination. For genetic study, ideally two of three frozen materials are kept — myocardium; spleen, liver or thymus; blood in EDTA or in a plain tube. Optimal storage is rapid freezing at −80 °C, without chemical treatment, preferably of liver or spleen; a DNA and RNA stabilising reagent allows fresh tissue to be transported at room temperature for a few days, and as a last resort extraction may be attempted from formalin-fixed or paraffin-embedded tissue, from samples collected for toxicology or from blood collected during life. Toxicology (peripheral and cardiac blood, urine, bile, gastric contents) is recommended in all cases, although a positive result does not exclude a cardiac cause or contribution, and tracings from emergency monitors and the external defibrillator, as well as pacemaker or ICD memories, should be retrieved. The cause is discussed at a meeting of pathologist, forensic physician, cardiologist and clinical geneticist [13]. In France, samples collected in a judicial context may be used for scientific purposes only with authorisation from the public prosecutor, requested by the family or by the forensic team in agreement with a reference centre; analysis requires the family's consent, that of a single family member being sufficient, and the conclusions are communicated after the judicial seals are lifted, unless there is a local agreement with the prosecutor [13].

The yield depends on the context. Combining genetic analysis of the deceased with clinical assessment of first-degree relatives, the cause is identified in 20–40% of sudden deaths occurring before 40–45 years of age and in about 20% when the autopsy is negative; when the autopsy shows macroscopic and microscopic cardiomyopathy, genetic analysis of the deceased identifies the cause in about 35–40% [13]. With an autopsy suggestive of cardiomyopathy, testing is directed at that hypothesis; with a negative autopsy, a predefined panel covering both cardiomyopathy and rhythm disorder genes is used, agreed by consensus within the CARDIOGEN filière and periodically updated, and the result offers an aetiological lead without establishing it. Broad untargeted panels, exome and genome are not recommended for counselling relatives, because of the risk of overinterpreting VUS; a VUS found in the deceased is not used for family screening, its disclosure to the family should be weighed against the psychological burden without direct benefit, and segregation with the appearance of a phenotype in clinically followed relatives is the means of reassessing it [13]. In the survivor of cardiac arrest, investigation includes electrolytes, troponin, inflammatory markers, toxicology, ECG with high precordial leads, continuous ECG monitoring for at least 24 hours, exercise testing, echocardiography, cross-sectional imaging and coronary angiography. The ECG obtained immediately after resuscitation should be read with caution, because repolarisation may mimic acute coronary syndrome, long QT or Brugada syndrome, and post-arrest hypokalaemia does not explain the event. CMR looks for MINOCA, myocarditis, fibrosis and early cardiomyopathy, including arrhythmogenic left ventricular cardiomyopathy, often invisible on other tests; the electrophysiological study is reserved for specific suspicions, such as arrhythmogenic right ventricular cardiomyopathy (with voltage mapping), ablatable Purkinje ectopy or equivocal pre-excitation. Genetic testing is systematic, with the patient's agreement, when the investigation suggests a genetic disease explaining the arrest; with a completely negative work-up (idiopathic ventricular fibrillation), a panel of arrhythmia and cardiomyopathy genes may be offered, following a prior decision with the geneticist, bearing in mind that the yield is low and interpretation difficult [13].

5.4. Practical algorithm

1. Confirm phenotype (LVEF, dimensions, CMR) and exclude sufficient acquired causes, recognising these do not exclude genetic predisposition [1, 5].
2. Obtain at least three-generation pedigree, warning signs and extracardiac involvement [1, 12].
3. Offer counselling/testing to the most clearly/severely affected relative; core DCM panel or exome/genome in children and syndromic forms [5, 12].
4. Pathogenic/likely pathogenic variant: confirm affected segregation where possible, apply gene-specific risk stratification and offer cascade testing [1, 2].
5. VUS: familial clinical screening, segregation only in affected relatives and periodic review [1, 5].
6. Negative: maintain first-degree clinical screening and consider reanalysis [1, 2].

Book Figure 5.2 summarises these steps, adding that with a merely likely pathogenic variant, variant-negative relatives should retain infrequent cardiac assessment in case it is not causal [1].

6. Differential Diagnosis

Below age 10, investigations include Holter, CK, plasma carnitine, acylcarnitines, glucose (supervised fasting studies if needed), lactate, ammonia, differential blood count (Barth neutropenia), lactate dehydrogenase, cholesterol/urate, urinary organic/dicarboxylic acids, cardiolipin in boys, brain MRI with neurological involvement, genomic testing and possible muscle biopsy [47]. Recognising primary carnitine deficiency has immediate therapeutic consequences because L-carnitine can save life [47]. In Saudubray's metabolic disorders, DCM is major in multiple dolichol synthesis/recycling defects and COG7-CDG; infantile PMM2-CDG may present with pericardial effusion tamponade, and isolated isobutyryl-CoA dehydrogenase deficiency has been described with DCM [55].

With weakness or raised CK, the Oxford Desk Reference recommends DMD deletion/duplication testing for X-linked history and promoter variant/exon 29 deletion testing in young men without weakness [8]. Genetic neuromuscular-associated DCM, or DCM without an identified genetic cause, warrants investigation for subclinical neuromuscular disease; conversely, neuromuscular disease associated with cardiac involvement warrants cardiology referral [35].

7. Treatments and Risk Management Strategies

7.1. General principles

Genetic DCM pharmacotherapy follows chronic heart failure (HF) recommendations: ESC 2023 refers to ESC 2021 HF guidance, independent of aetiology and therefore generic rather than genetic DCM-specific, reaffirmed by ESC 2026. The book summarises ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and beta-blockers for all, mineralocorticoid receptor antagonists (MRAs) in NYHA II–IV with LVEF ≤35%, diuretics for symptoms, correction of aggravators (ischaemia, hypertension, valve disease) and devices after maximal treatment [1, 4, 5]. ESC 2021 recommends ACEI, beta-blocker, MRA and dapagliflozin/empagliflozin in reduced-EF HF to reduce hospitalisation/death (I, A), and sacubitril/valsartan replacing ACEI (I, B); in mildly reduced EF, these except diuretics were IIb, C [51]. The 2023 focused update revised mildly reduced/preserved EF guidance after empagliflozin/dapagliflozin trials with LVEF >40% [56]. Updated reduced-EF therapy consolidated ARNI, beta-blocker, MRA and SGLT2 inhibitor quadruple therapy: a network meta-analysis of 89 trials (103,754 patients, searched to April 2025) found all-cause mortality HR 0.39 versus placebo (95% CI 0.32–0.49), equivalent to 5.3 life-years gained for a representative 70-year-old [57]. No HF trial was genotype-stratified; familial DCM evidence is extrapolated from general HF populations [7, 58].

Response appears gene-dependent. TTNtv patients generally recover systolic function more during initial years, potentially attenuating over time; other genes tend to respond less than genetically negative patients [5]. A Norwegian study published August 2026 followed 712 genotype-positive DCM/NDLVC patients (mean age 40, 52% female, 20% probands) for 3.1 years; only 6% of 407 with preserved/mildly reduced LVEF fell below 40%; among 130 mildly reduced patients, HF treatment was associated with 1.8 percentage points higher LVEF (95% CI 0.7–2.9), and 2.4 in high-risk genotypes [59]. This observational study is susceptible to confounding by indication and presented as a basis for future trials.

7.2. Medicines, dosing and label differences

Doses are from consulted official labels; unlabelled paediatric use (e.g. beta-blockers or SGLT2 inhibitors in paediatric DCM) is off-label and depends on specialist protocols [64, 70]. In laminopathies with block, conduction-worsening medicines—beta-blockers, calcium channel blockers and others—should be avoided without a pacemaker or ICD [6]. ESC 2021 recommends cardiac resynchronisation for symptomatic sinus-rhythm HF with LVEF ≤35% despite optimisation and QRS ≥150 ms with left bundle branch block (I, A); consider with QRS ≥150 ms without left block or 130–149 ms with it (IIa, B), possibly with QRS 130–149 ms without left block (IIb, B), and not with QRS <130 ms without high-grade AV pacing indication (III, A). In reduced-EF HF requiring ventricular pacing for high-grade AV block, resynchronisation is recommended over RV pacing regardless of NYHA or QRS width (I, A) [51]. This is particularly relevant to laminopathies with AV block.

7.3. Comparative regulatory status

Sources: Drugs@FDA, FDA labels and EMA EPAR/medicines database accessed on 6 October 2026 [60, 61, 73–78]. Authorisation does not imply reimbursement or availability in each country; funding is decided in Portugal by INFARMED and in Brazil by ANVISA/CONITEC.

7.4. Sudden death prevention and devices

DANISH randomised 1116 non-ischaemic systolic HF patients with LVEF ≤35% to ICD or usual care (58% resynchronisation in both): after median 67.6 months, all-cause mortality was 21.6% versus 23.4% (HR 0.87; 95% CI 0.68–1.12; p = 0.28), although sudden death halved (4.3% versus 8.2%; HR 0.50) [79]. This and malignant arrhythmias above LVEF 35% in some genes prompted multiparametric strategies.

Full guideline reading resolves apparent threshold differences. ESC 2022 uses LVEF <50% for DCM/HNDC with ≥2 factors, genotype (LMNA, PLN, FLNC, RBM20) being one, and requires LMNA five-year risk ≥10% plus manifest cardiac phenotype [48]. ESC 2023 sets no lower LVEF bound for high-risk genotypes: recommendations apply to LVEF >35% with additional gene-specific Table 21 factors—LMNA calculator; late enhancement or LVEF <45% in truncating FLNC, DSP, RBM20; calculator, LVEF <45%, enhancement or NSVT in PLN; male sex, or in women LVEF <45%, NSVT, enhancement or >200 ventricular premature beats on 24-hour Holter in TMEM43 [4]. ESC 2023 lists NSVT, frequent ventricular ectopy, male sex, significant enhancement and the specific variant among additional factors, recommends available calculators and, instead of ESC 2022's LMNA 10% five-year threshold, proposes real-world/preference-based shared decisions, citing validation where 7% overestimated risk (specificity 26%, C-statistic 0.85) [4]. ESC 2026's attributed “LVEF <45% and enhancement” simplifies Table 21 predictors rather than reproducing the recommendation [4, 5]. US formulations (HRS 2019, HFSA 2018) retain gene-based LVEF <45% or ICD before <35% [12, 54]. ESC 2023 LVEF >35% recommendations have level C evidence, noting randomised ICD trials included only LVEF ≤35% [4]. Specific calculators are the most accurate available instruments. Wahbi's LMNA model, derived in 444 and validated in 145 patients (events 19.3% and 23.4%), includes male sex, non-missense variant, first-degree-or-higher AVB, NSVT and LVEF; five-year risk ≥7% captured 96.2% of events, reclassifying 28.8% relative to guidelines [44]. Its preceding 269-carrier European series found malignant arrhythmia only with ≥2 of NSVT, initial LVEF <45%, male sex and non-missense variant [43]. A truncating FLNC model from 308 carriers (19% events, 4/100 person-years) includes age, male sex, previous syncope, NSVT and LVEF, with AUC 0.76–0.78 and a non-linear LVEF relationship (lower risk above 58%), awaiting external validation [40]. PLN p.(Arg14del) and DSP calculators exist, but not RBM20 [5, 80]. General LMNA calculators may overestimate risk in milder variants [5].

With laminopathy pacing indications, ICD is preferred to pacemaker because sudden death risk accompanies block/bradyarrhythmia; chronic AF management attempts sinus restoration, anticoagulation and rate control, while symptomatic supraventricular arrhythmias receive medicines or ablation [6]. The neuromuscular textbook retains primary-prevention ICD with ≥2 factors in dominant Emery–Dreifuss/laminopathies, recognising prospective validation needs [35]. X-linked EMD warrants anticoagulation for all sustained supraventricular arrhythmias, even paroxysmal, irrespective of CHA2DS2-VASc [35]. The Oxford Desk Reference gives anticoagulation for AF, intracardiac thrombus, previous stroke or severe dilatation/dysfunction, and notes possible ventricular arrhythmia benefit from amiodarone without long-term benefit evidence [8].

The French PNDS on laminopathies with cardiac presentation (HAS, 2022) defines specific management for LMNA [15]. Atrioventricular conduction disease was present on the ECG in 32–57% of patients, at mean ages of 40–41 years, and progressed to complete AV block in 15–18% of cohorts. The indication for pacing follows the usual criteria. In a meta-analysis, however, 11% (10/84) of patients with a pacemaker died suddenly, mainly from ventricular arrhythmia. When there is an indication for permanent pacing, the PNDS therefore recommends a transvenous ICD rather than a pacemaker. The subcutaneous ICD is not recommended, because it does not pace and the risk of high-grade block is high. AF and flutter, paroxysmal or permanent, mandate systematic therapeutic anticoagulation, regardless of the CHA2DS2-VASc score. No studies compare rhythm control with rate control, but the PNDS prefers maintenance of sinus rhythm, because of the risk of worsening ventricular function. AF ablation appears less effective than in the general population: in one series, 7 of 8 patients had early recurrence, at a mean of 4 months. Antiarrhythmic drugs follow the general rules, respecting the contraindications created by LV dysfunction, conduction disease and ventricular hyperexcitability. Given the venous thromboembolic risk, the PNDS recommends proactive venous thromboprophylaxis in primary prevention and that this risk be weighed in the anticoagulation decision in secondary prevention [15].

For the prevention of sudden death, the PNDS considers the ICD mandatory in secondary prevention and rejects the LVEF <35% threshold, poorly sensitive in this disease, for primary prevention [15]. The initial series justified this strategy. In 19 patients who received an ICD for severe conduction disease (HV interval >70 ms, complete AV block or severe sinus node dysfunction), 8 (42%) had an appropriate shock over a median of 34 months. In a prospective cohort of 47 carriers, 21 received an ICD for significant conduction disease and 11 of them (52%) had appropriate therapy over a median of 62 months, 9 with LVEF ≥45% at the time of the event [15, 81]. The PNDS combines two validated strategies:

1. Four independent risk factors — male sex, NSVT on Holter, LVEF <45% and non-missense variant. With two or more factors, the risk justifies an ICD; with none or one, surveillance is sufficient. The rule was derived in 269 European patients and validated in a French cohort of 101 patients followed for 3.4 years (C-index 0.76). A man with a non-missense variant has two factors by definition, and the PNDS requires a case-by-case decision, according to cardiac expression and calculated risk.
2. Five-year absolute risk calculator for malignant arrhythmia (https://LMNA-risk-vta.fr/), which uses sex, AV block (absent, first-degree or high-grade), NSVT (three or more beats at ≥120 bpm), LVEF and variant type. The C-index was 0.77 in the initial cohort of 444 patients and 0.827 in the replication in 145. Most French teams apply a threshold of 10% at five years, the same as the 2022 ESC guidelines, and a direct comparison favoured the calculator [15, 44, 48].

The PNDS stresses that about 30% of patients with an ICD have complications at five years (inappropriate shocks, infections, lead fractures). The decision, particularly in a young patient with intermediate risk, should incorporate the preference of the informed patient. In recurrent VT despite antiarrhythmic drugs, substrate ablation may be offered, the mechanism usually being scar-related or bundle branch re-entry. In a multicentre series of refractory VT, however, there was recurrence in 91%, progression to end-stage HF in 44% and mortality of 26%, attributed to a diffuse, basal septal and intramural substrate. Amiodarone and treatment in a centre experienced with intramyocardial substrate are recommended. Rhythm management should not delay transplant planning when there is recurrent VT with systolic dysfunction [15].

Table sources: [4, 6, 15, 35, 48, 54].

7.5. Advanced disease, recovery and physical activity

Heart transplantation and mechanical ventricular support are options for refractory end-stage failure [6, 8]. Patients with genetic DCM have favourable outcomes after transplantation, attributed to younger age and fewer comorbidities [58]. Recovery of function is not cure: in the TRED-HF trial, 40% of patients with recovered DCM relapsed in the short term after treatment withdrawal; at long-term follow-up (median 6 years), 65% (33/51) relapsed, with a five-year relapse rate of 61% from enrolment, one-third with identifiable triggers, including arrhythmia and pregnancy [82, 83]. The consensus recommendation is to maintain therapy even with recovered LVEF [58]. In laminopathy, the French PNDS recommends general HF therapy (beta-blockers, ACEI, ARB or sacubitril/valsartan and gliflozins), acknowledging that the specific efficacy in this population is unknown [15]. Resynchronisation follows the general criteria, with a response, in terms of stabilisation of LVEF and HF, in 38–62% of patients. In severe HF or significant left or right ventricular dysfunction, early referral to an advanced HF centre is recommended, because progression is faster than in other aetiologies. The aim is to optimise treatment, assess circulatory support or transplantation and avoid complications before these are carried out. In a report of seven transplanted patients from a family with limb-girdle dystrophy 1B, there were no more early or late complications than in other transplant recipients over a mean follow-up of 8 years (1–17), nor rhabdomyolysis or notable muscle deterioration. The PNDS concludes that mild skeletal muscle involvement does not contraindicate transplantation [15]. Therapeutic education programmes for HF and the ICD are part of treatment, and the attending physician monitors adherence and family surveillance in liaison with the centre [15].

The 2023 ESC guidelines recommend regular low-to-moderate-intensity exercise in all individuals with cardiomyopathy who are able to do it and an individualised risk assessment for exercise prescription in all patients (both class I, level C) [4]. In DCM and NDLVC, moderate- and high-intensity exercise should be considered in genotype-positive, phenotype-negative individuals who wish to do it, except with pathogenic variants in LMNA or TMEM43 (IIa, C); high-intensity exercise and competitive sport may be considered in a selected group of optimally treated asymptomatic patients with LVEF ≥50% without complex exercise-induced arrhythmias (IIb, C), and moderate exercise in optimally treated asymptomatic patients with LVEF 40–49% under the same conditions (IIb, C); high-intensity exercise, including competitive sport, is not recommended in symptomatic patients, with LVEF ≤40%, exercise-induced arrhythmias or pathogenic variants in LMNA or TMEM43 (III, C) [4]. The 2022 ESC guidelines likewise do not recommend high-intensity exercise, including competitive sport, in DCM/HNDC with an LMNA variant (III, C) [48]. The French PNDS bases the restriction in laminopathy on experimental and clinical data. In the murine model, intense exercise brought forward DCM. In patients, competitive sport was an independent predictor of sudden death or severe HF events, and cumulative lifetime physical activity was associated with systolic dysfunction and higher NT-proBNP [15]. Hence its recommendations: contraindicate competitive sport when there is cardiac expression, particularly with DCM or ventricular hyperexcitability; restrict sustained high-intensity activities; avoid excessive sedentary behaviour; and, in carriers without cardiac expression, decide case by case, competition usually being discouraged. These recommendations coincide, in substance, with the exception that ESC 2023 makes for LMNA in genotype-positive, phenotype-negative individuals [4, 15]. Avoidance of excessive alcohol consumption is recommended in TTNtv carriers, as it is a documented trigger [5, 26]. Before non-cardiac surgery, patients with neuromuscular disease and cardiac involvement require attention to arrhythmias and conduction defects that may be precipitated perioperatively; in Emery–Dreifuss dystrophy, suxamethonium and halogenated volatile anaesthetics should be avoided [7, 35]. The French PNDS extends this precaution to any laminopathy with overt muscle involvement, because of the theoretical risk of malignant hyperthermia: avoid the depolarising muscle relaxant (suxamethonium) and volatile anaesthetics (halothane, isoflurane) [15].

Extracardiac involvement in laminopathies has its own treatment [15]. In LMNA-associated lipodystrophy, a diet adapted to body mass index, low in high-glycaemic-index sugars and saturated fats, and regular non-intensive exercise after excluding cardiovascular contraindication are recommended. Metformin can be started as soon as fasting glucose is >1 g/l or glucose intolerance is present. The PNDS (French National Diagnosis and Care Protocol) does not state the dose; the US label for immediate-release tablets, approved for type 2 diabetes and used here by extrapolation, provides in adults 500 mg twice daily or 850 mg once daily, with meals, with increases of 500 mg per week or 850 mg every 2 weeks up to a maximum of 2,550 mg/day in divided doses. From age 10, the label provides 500 mg twice daily, with weekly increases of 500 mg up to 2,000 mg/day. Initiation is not recommended with eGFR between 30 and 45 ml/min/1.73 m², and the drug is not used below 30 [84]. The LDL cholesterol target in primary prevention is <1 g/l (2.58 mmol/l) without diabetes and <0.7 g/l with diabetes, which often justifies a statin; fibrates are used in hypertriglyceridaemia. Contraception should take metabolic risk into account, and metreleptin is discussed case by case at the multidisciplinary meeting of the PRISIS network. There is no specific treatment for muscle involvement. The PNDS provides for stepwise analgesia, relaxants and massage for myalgia and cramps and, in advanced forms, motor physiotherapy with stretching and gentle strengthening. It also provides for technical aids (canes, orthoses, walker, wheelchair), surgery for contractures (especially Achilles) and severe scoliosis, and respiratory physiotherapy with cough assistance or non-invasive ventilation. In LMNA-related congenital muscular dystrophy, some patients appear to respond to corticosteroids, but the data are unpublished. In progeroid syndromes, lonafarnib, alone or combined with pravastatin and zoledronic acid, improved weight, vascular stiffness, bone structure and hearing in two non-randomised controlled studies, with little or no effect on survival [15].

7.6. Clinical trials and investigational therapies

The trials should not be compared with one another: they differ in population, design (open-label or blinded), duration and endpoints (functional, imaging or event-based). The danicamtiv trial measures a change in LVEF in an open-label cohort without placebo and therefore does not demonstrate clinical benefit; the i-PHORECAST trial did not recruit the planned sample size and does not exclude a modest effect; and in VICTOR, since the primary endpoint was negative, the secondary analyses are nominal [86–88]. GeneReviews still presents p38 inhibition as an investigational therapy; the REALM-DCM results, published in 2024, closed that line [6, 85]. The French PNDS, written while REALM-DCM was still under way, also listed mTOR pathway inhibitors, which improved remodelling and systolic function in murine models of laminopathy, and platelet-derived growth factor receptor (PDGFR) blockers, with the potential to correct rhythm abnormalities in in vitro models. It also mentioned variant-specific preclinical strategies: gene therapy to compensate for haploinsufficiency and gene correction by CRISPR-Cas9, both with no foreseeable timeline for reaching the clinic [15]. The first clinical translation of compensatory gene therapy is the phase 1/2 NVC-001 trial, shown in the following table [89].

All programmes are registered/recruiting without published results at review date; a previous ACEI prevention trial in presymptomatic carriers (perindopril, NCT01583114) terminated with six participants [96]. ClinGen and i-PHORECAST authors emphasise the absence of validated prevention in asymptomatic carriers [7, 87].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In dominant DCM, each carrier's child has a 50% chance of inheriting the variant without predictable onset/severity because of reduced penetrance and variable expressivity [2, 6]. Some patients have an affected parent; de novo frequency is unknown, with up to one-third in family-history-negative children [2, 12]. Both lineages matter because bilineal DCM and variants inherited from both parents occur; if both carry DCM-related variants, siblings have 75% chance of inheriting one or two and 25% neither [2]. If parental leucocytes lack the proband variant with confirmed parentage, sibling risk is approximately 1% because of germline mosaicism, not detected by leucocyte testing [6]. Untested parents' absence of symptoms does not reduce sibling risk, treated as up to 50% [6].

In recessive JPH2/TNNI3 DCM, parents are obligate heterozygotes and siblings have 25% risk of both variants; because the same variants may confer dominant risk, surveillance is reasonable for parents, heterozygous siblings and proband offspring [2]. DMD is X-linked: men have syndromic or isolated DCM, while carriers may develop DCM with cumulative 7–10% risk [2, 35]. Mitochondrial forms may be matrilineal, recessive or sporadic [47].

8.2. Family screening and predictive testing

Proband P/LP identification enables targeted familial testing regardless of age or phenotype after formal counselling; non-carriers usually no longer have increased risk, but discharge is individualised because multiple gene variants may coexist [1, 2, 5]. For a merely likely pathogenic variant, the book advises regular carrier assessment and infrequent non-carrier assessment [1]. Negative, inconclusive or VUS-only results do not support cascade testing; maintain first-degree clinical screening [1, 5, 14]. ESC 2023 grades this: cascade testing with pre-/post-test counselling recommended for at-risk adults with P/LP (I, B), considered in paediatric relatives weighing cardiomyopathy, expected onset, familial presentation and clinical/legal consequences (IIa, B); familial VUS testing in parents/affected relatives for segregation considered if it enables confident interpretation (IIa, C); diagnostic genetic testing not recommended in phenotype-negative relatives without familial P/LP (III, C) [4]. After cascade testing, first-degree carriers require multiparametric ECG/imaging and prolonged follow-up (I, B); phenotype-negative non-carriers should be discharged with advice to return for symptoms/new familial information (I, C). Without proband P/LP or testing, baseline first-degree clinical assessment is recommended (I, C), and regular long-term assessment should be considered (IIa, C); after a first-degree relative dies, consider assessing their close relatives (IIa, C) [4]. The text allows ending periodic surveillance at ≥50 with normal tests in informative families where only the proband is affected and testing negative [4]. ESC 2022 recommends first-degree ECG/echo when proband diagnosis was before 50, hereditary clues exist or familial DCM/HNDC/premature sudden death is present (I, C), and permits these in apparently sporadic relatives (IIb, C) [48].

TTNtv algorithms derive from 413 relatives across seven centres (301 with median 5.7-year follow-up): 24.6% developed dysfunction/dilatation, 17.3% DCM and 5.3% major events after diagnosis; age ≥30, male sex and partial DCM predicted progression [97]. This September 2026 model is not yet incorporated into guidelines. Among relatives of DCM/peripartum women in the DCM Precision Medicine Study (665 relatives, 452 probands), DCM/partial DCM risk was similar (HR 0.77; 95% CI 0.47–1.28), and estimated prevalence in lower-risk relatives exceeded UK Biobank estimates, supporting genetic/familial evaluation in all peripartum patients [98]. Minimum assessment includes history, examination, ECG and echo; the book acknowledges no multicentre trials demonstrating early treatment efficacy in early-disease relatives [1].

Predictive testing in minors follows paediatric recommendations; estimated detectable childhood LMNA presentation is approximately 1.4%, but testing identifies children benefiting from early treatment and justifies tighter screening with aggressive early familial disease [6]. Counselling should cover uncertainty-related distress, anxiety in unaffected carriers, employment, mortgages and insurance, childbearing and occupational decisions; psychological support should be offered, with patient organisations contributing [1, 5]. Specialist cardiologists, clinical geneticists and counsellors should collaborate [1].

For laminopathies, the French PNDS details the organisation of counselling and family screening [15]. The diagnosis is communicated at a dedicated cardiology and genetics consultation. This consultation explains the chronic heart disease, the possibility of extracardiac involvement and the genetic origin, organises information for relatives and provides the contact details of patient associations. The pedigree covers at least three generations, and the information includes the usually late expression, after 20 years of age and sometimes only at 40–50, and the rarity of non-penetrance. Predictive testing is offered only with a class 4 or 5 variant in the proband and is recommended for all first-degree relatives from 10–12 years of age, or earlier if there are early-onset forms in the family. Non-carriers may end specific surveillance, and those who decline to know their status continue regular cardiological surveillance. Clinical screening may run in parallel with testing or depend on its result. Without testing, it includes at least ECG, echocardiogram and 24-hour Holter from 10–12 years of age, repeated every 2–3 years between 10 and 20 years and every 2–5 years thereafter, usually up to 60 years of age [15].

The French legal framework conditions these steps [15]. The team may not contact relatives directly: the information passes through the proband, who may be given a written information sheet. Refusal to inform the family may engage the proband's civil liability (Decree No. 2013-527 of 20 June 2013), and in complex cases a partial information procedure may be discussed. Testing a relative is part of the genetic counselling provided for in Article L1131-1-2 of the Public Health Code. In the proband it requires written consent, a certificate from the clinician, a test prescription, pedigree and clinical data for a certified laboratory. Predictive testing may be prescribed only by physicians in a multidisciplinary team declared to the Agence de la biomédecine (Decree No. 2008-321 of 4 April 2008), with a clinical geneticist mandatory.

When DCM is sought in a family following a sudden death, the French PNDS on sudden death in the young defines the assessment of relatives [13]. If the autopsy found no cause, or was not performed and the deceased was younger than 45 years without an evident explanation in the clinical history, assessment is offered to all first-degree relatives, with particular attention to both parents, within a multidisciplinary programme; the indication stands even when the death occurred long ago, and is reinforced by documented ventricular arrhythmia at the time of death or a personal or family history suggestive of inherited arrhythmic disease. From 15 years of age, the complete assessment includes ECG, echocardiogram, exercise testing with QT analysis at the fourth minute of recovery, Holter, ECG with electrodes in the 2nd and 3rd intercostal spaces, mental stress testing, standing ECG in adults and, if possible, an ajmaline test, with CMR depending on the findings; before 15 years of age it is limited to ECG, Holter, echocardiogram and exercise testing if age allows. If the cause has been identified, screening is directed at that disease in all first-degree relatives and extended to second-degree relatives when a first-degree relative is not available, with prior probabilities of 50% and 25% in dominant inheritance; genetic testing in minors is reserved for cases in which the result immediately changes management. Without an identified familial variant, genetic testing of asymptomatic relatives is strongly discouraged, because a negative result does not exclude future disease and broad panels generate VUS; the DNA of assessed relatives may be stored for later use [13]. Because the penetrance of cardiomyopathies is reduced and late, a negative initial assessment does not exclude disease: repetition of ECG and echocardiogram every 3–5 years up to 45 years of age is proposed, and the PNDS notes that a cardiomyopathy may be expressed only at 50–60 years when the deceased was not fully investigated. In children without a complete assessment, ECG and echocardiogram are repeated every 3–4 years (about 4 in the summary) until the complete assessment at 15 years. A complete and negative assessment, in the deceased (with autopsy) and in the relative, is reassuring and makes specific follow-up unnecessary, without lifestyle restrictions, but with advice to seek prompt consultation in case of syncope or palpitations [13]. The same document stresses that the occurrence of sudden death in the family rarely changes the individual prognosis, except in diseases such as hypertrophic cardiomyopathy, which should prevent therapies more aggressive than those indicated for the genotype and phenotype [13].

Psychological support is part of this assessment [13]. After a sudden death in the young, about 21% of first-degree relatives develop prolonged grief or persistent complex bereavement disorder, versus about 7% of the bereaved population in general, and 44% have post-traumatic stress symptoms, situations that require support because of the increased risk of other psychiatric comorbidities, suicide and chronic disease. In an analysis of the needs of parents who had lost a child, psychological support was the least met need, and about three-quarters wanted access to professional counselling. Disclosure of a hereditary cause brings relief, but may generate guilt in the transmitting parent, so the possible scenarios (identified disease, VUS, no result) should be discussed from the outset. In France, the national psychological resource centre of the CARDIOGEN filière supports teams and maintains a directory of regional psychologists trained in inherited arrhythmic diseases and sudden death [13].

Table sources: [4–6, 8, 12, 13, 15, 52].

8.3. Prenatal and preimplantation diagnosis

Once the familial pathogenic variant has been identified, prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing (PGT-M) are possible; the ideal time to discuss these options is before pregnancy [5, 6]. Demand is low: in the Netherlands, between 2001 and 2015, eight prenatal diagnoses were performed for inherited cardiac diseases, two of them for DCM, always in families with a severe phenotype or sudden death; between 2006 and 2010, 24 PGT cycles for inherited cardiac diseases were recorded in Europe, one for DCM, and there are reports of PGT for LMNA-related DCM [99]. PGT requires in vitro fertilisation, with increased perinatal risks, and development of a specific assay that may take time; non-invasive prenatal diagnosis was not available for inherited cardiac diseases at the date of the source consulted [99]. Perspectives on the use of these options differ between professionals and families, and the decision is personal [6]. In France, prenatal diagnosis is authorised only for diseases of particular severity that are incurable (Article L2131-1 of the Public Health Code), and preimplantation diagnosis follows the same legislation. According to the laminopathy PNDS, multidisciplinary prenatal diagnosis centres rarely accept requests for cardiomyopathy, but accept them more readily for myopathies or complex forms, deciding case by case in particularly severe forms or with variants of known deleterious effect [15]. The PNDS on sudden death in the young is more restrictive: since most of the diseases concerned have effective prevention of sudden death, it considers that prenatal or preimplantation diagnosis is not indicated except in very particular situations, such as families with very high sudden mortality and a disease with poorly effective treatment, giving as examples long QT type 3, some catecholaminergic polymorphic ventricular tachycardias and sudden deaths linked to DPP6 [13].

8.4. Pregnancy

GeneReviews states that pregnancy is contraindicated in women with DCM, because of the significant increase in mortality, and that the pregnant woman with DCM should be followed in high-risk obstetrics; at-risk women with unknown genetic status should have cardiovascular assessment and counselling before pregnancy [6]. The 2023 ESC guidelines recommend, with class I and level C, risk assessment and counselling before pregnancy in all women using the mWHO maternal risk classification, contraceptive counselling for women of reproductive age and their partners, counselling on the risk of transmission for men and women before conception, prior review of medication for safety in pregnancy, vaginal delivery in most women unless there is an obstetric indication, severe HF (EF <30% or NYHA III–IV), severe obstruction or labour on oral anticoagulation, and therapeutic anticoagulation with low-molecular-weight heparin or vitamin K antagonists, according to trimester, in AF; continuation of beta-blockers in pregnancy, with surveillance of fetal and neonatal growth, and genetic counselling and testing in peripartum cardiomyopathy should be considered (IIa, C) [4]. The text adds that preconception counselling should be provided by a multidisciplinary team (“pregnancy heart team”) and that, in women in mWHO classes II–III, III and IV (including EF <35%), pregnancy and delivery should take place in a specialised centre [4]; the 2025 ESC guidelines on cardiovascular disease and pregnancy are the current European document for this decision, whose full text was not consulted [100]. Drugs acting on the renin–angiotensin system, including sacubitril/valsartan, cause fetal toxicity in the second and third trimesters, ivabradine and vericiguat may cause fetal harm (the latter contraindicated in pregnancy in the US label), dapagliflozin is not recommended in the second and third trimesters and spironolactone affects sexual differentiation in animals; beta-blockers may cause neonatal hypotension, bradycardia and hypoglycaemia when used in the third trimester [60, 64, 66, 69, 73, 75]. Review of the treatment regimen should therefore precede conception. In the TRED-HF follow-up, pregnancy was among the triggers of relapse [83]. For LMNA, data are scarce and less unfavourable than the general GeneReviews contraindication. In five women at an early stage of cardiomyopathy and without HF, all relatives of patients, pregnancy proceeded without life-threatening arrhythmia. In a series of 89 pregnant carriers, new arrhythmias occurred in 9%, without serious maternal or fetal complications, and a previous pregnancy did not worsen the prognosis. The PNDS recommends close cardiological surveillance during pregnancy, with echocardiography (dimensions and LVEF), Holter and NT-proBNP, at intervals determined by symptoms and clinical status, and allows treatment and mode of delivery to be adjusted [6, 15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and the entity measured

The distinction matters: TTNtv carrier prevalence greatly exceeds disease prevalence because approximately 3% of controls carry them; variant frequency is not disease frequency [2, 7]. Section 2.2 fractions concern nonsyndromic DCM patients rather than the general population.

9.2. Ancestry, sex and founder populations

The US DCM Precision Medicine Study included many Black patients (43.1% of 1220 probands). Estimated familial prevalence was 11.3 percentage points higher in Black than White probands, with higher first-degree risk in non-Hispanic Black families (HR 1.89; 95% CI 1.26–2.83); cumulative familial DCM risk reached 19% by 80, or 33% including partial phenotypes [22]. However, African-ancestry patients had fewer actionable variants (8.2% versus 25.5% European ancestry), mainly fewer TTNtv/other loss-of-function variants and more missense VUSs; published pathogenicity evidence was weaker for African-only variants [102]. These indicate clinical database under-representation rather than lower heritability and reduce negative-test exclusion value in African ancestry.

In Europe, the Finnish series of 145 patients had a diagnostic yield of 35.2%, with TTNtv in 20.6% of familial and 14.6% of sporadic forms [53]. The PLN p.(Arg14del) variant is a Dutch founder effect, with 868 carriers in a national cohort and major-event penetrance of 43–70% by 70 years of age [33, 41]; the Dutch DES variant NM_001927.4:c.38C>T p.(Ser13Phe) is associated with right ventricular involvement and conduction disease [7, 29]. The contribution of some muscle genes varies by region: FKRP-related LGMD2I accounts for 8% of families with limb-girdle dystrophy in the Netherlands and is the most frequent form in the United Kingdom and Denmark; Fukuyama congenital muscular dystrophy is frequent in Japan and rare in the West [35]. The Brazilian textbook of genetic syndromes includes familial DCM in its table of adult genetic diseases, with TNNT2, TTN, MYH7, sarcoglycans and dystrophin, without national epidemiological data [103]. No epidemiological or founder-effect data specific to Portugal or Brazil for familial DCM were found in the sources consulted, which does not demonstrate that they do not exist.

Sex modifies expression: DCM is more frequent in men, TTNtv onset earlier in men, DSP and non-TTN sarcomeric variants predominate in women; male sex predicts arrhythmic risk in LMNA, FLNC, DES and progression in BAG3/TTNtv [7, 30, 37, 40, 44, 97].

9.3. Children and special populations

Paediatric DCM has more diverse aetiology, more syndromic/metabolic/neuromuscular causes and recessive/X-linked/mitochondrial inheritance; broader specialist-centre investigation is required [1, 12]. Non-TTN sarcomeric variants predominate in isolated paediatric DCM, particularly infancy [37]. Peripartum, alcoholic, chemotherapy- and myocarditis-associated populations frequently have genetic predisposition (8–18%), justifying genetic/familial assessment [5, 26–28].

9.4. European networks and patient organisations

The relevant European Reference Network is ERN GUARD-Heart (rare, low-prevalence and complex diseases of the heart), cited in the Dutch endorsement of the European guidelines [14]. The resources listed by GeneReviews and the Oxford Desk Reference include Cardiomyopathy UK, the DCM Foundation, the Children's Cardiomyopathy Foundation, the SADS Foundation (sudden arrhythmic death syndromes), the Dilated Cardiomyopathy Research Project at Ohio State University, the American Heart Association and MedlinePlus [2, 6, 8]. In France, laminopathies with cardiac presentation are followed within the national health filière CARDIOGEN (inherited or rare heart diseases, www.filiere-cardiogen.fr) [15]. The coordinating reference centre for inherited or rare cardiomyopathies and rhythm disorders is at the Pitié-Salpêtrière Hospital (Paris). The constituent centres include the neuromuscular centre of Cochin Hospital and the Ambroise-Paré, Bichat, European Georges-Pompidou, Henri-Mondor and Necker hospitals in Paris, as well as Nantes, Bordeaux (CMARY) and Lyon; there are competence centres in all regions, including Guadeloupe and Réunion (www.cerefcoeur.fr). Muscle involvement is managed through the FILNEMUS filière and metabolic involvement through the PRISIS network. The patient associations are the Ligue contre la cardiomyopathie, AFM-Téléthon and APODEC, for defibrillator carriers, and the filière has a national psychological resource centre. The attending physician refers suspected cases to these centres and coordinates treatment and family surveillance with them [15]. The 2022 PNDS on sudden death in the young was coordinated by the reference centre for inherited arrhythmic diseases of the West (Nantes University Hospital), with the reference and competence centres of Paris, Lyon, Bordeaux, Toulouse, Rennes and Lille and the associations AMRYC and Les Maux du Cœur. It assigns the family physician a decisive role, because the search for an explanation often arises long after the death, and provides for the involvement of school and occupational physicians in follow-up, support in dealings with insurers and in schooling, and drafting of the care protocol with the attending physician in the event of an application for exemption from patient co-payment for a condition not on the list [13].

10. Illustrative Clinical Case

10.1. Published case: smartwatch bradycardia alerts and LMNA cardiomyopathy

Rushakoff and colleagues (2025) described a 47-year-old Costa Rican-born man, asymptomatic and exercising vigorously several times weekly, referred after recurrent smartwatch bradycardia alerts [46]. Family history included a younger brother with exertional syncope dying of HF in his twenties, a sister diagnosed with ventricular ectopy at the same age and a mother with bundle branch block; no known neuromuscular disease. Three years earlier after his brother's death, CMR showed LVEF 53% and linear septal fibrosis, prompting ACEI initiation [46].

He had bradycardia with irregular pulse, BP 127/72 mmHg and no murmur/oedema. ECG showed sinus bradycardia, marked first-degree AVB and multiform ventricular premature beats (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC12412439/figure/ytaf415-F1/). Echo showed a non-dilated LV (end-diastolic diameter 5.2 cm), LVEF 35%, global longitudinal strain −10.2%, mild RV dysfunction and mild-to-moderate mitral regurgitation. Seventy-two-hour Holter recorded 56 pauses (longest 4.9 s), third-degree, 2:1 and second-degree type 1 AVB. Differentials were sarcoid, viral/giant-cell myocarditis and Chagas given Central American origin. Inpatient CMR showed LVEF 32% and mid-wall basal/mid-septal and adjacent basal inferior enhancement (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC12412439/figure/ytaf415-F2/) [46].

A resynchronisation defibrillator (CRT-D) was implanted for low LVEF, non-ischaemic cardiomyopathy and familial sudden death; spironolactone 25 mg/day, lowest-dose sacubitril/valsartan (reported as “24–25 mg” twice daily; corresponding commercial strength 24/26 mg) and dapagliflozin 10 mg/day were initiated. Genetic testing identified pathogenic LMNA c.364A>T p.(Lys122*), corresponding in ClinVar to NM_170707.4:c.364A>T (p.Lys122Ter), pathogenic by multiple submitters without conflict [29, 46]. Device interrogation found AF burden 8.7%; authors initiated apixaban despite CHA2DS2-VASc 0, citing laminopathy atrial myopathy thromboembolic risk. At six months LVEF was 40–45%, with continued asymptomatic status and no shocks [46].

The case illustrates the typical sequence of laminopathy (conduction disease and arrhythmia before or alongside dysfunction), the value of a family history of sudden death and pacemaker implantation, and the role of the genotype in device selection, consistent with the preference for an ICD when there is a pacing indication [6]. Two decisions must be read in context: anticoagulation with a CHA2DS2-VASc score of 0 reflects an individual decision by the authors, without a specific guideline recommendation cited in the article, and the authors' references to the guidelines require correction: they attribute to the 2021 ESC heart failure guidelines a class I recommendation for genetic testing in DCM with AV conduction delay before the age of 50 or with a family history, but that wording, with class I and level B, appears in the 2022 ESC guidelines on ventricular arrhythmias, whereas the 2021 guidelines indicate testing in all patients with DCM without assigning a class [48, 51]; and the 2019 HRS consensus considers an ICD “reasonable” (class IIa) in laminopathy with two or more of LVEF <45%, NSVT and male sex, or with a pacing indication, and does not “recommend” it as the authors write [54]. The article does not describe genetic testing in the assessment carried out after the brother's death, when CMR already showed septal fibrosis; this sequence is recorded here as an illustration that testing the first relative assessed can bring stratification forward, without attributing that interpretation to the authors.

11. Prognosis and Long-Term Follow-up

The prognosis of DCM has improved with modern treatment, but mortality remains 20% at five years and 35% at ten years in the series cited by the textbook, and DCM continues to be the main indication for transplantation [1]. A positive genotype is associated with a worse overall course, with more major cardiovascular events, end-stage failure and malignant arrhythmias, and trajectories differ by gene: arrhythmic predominance in LMNA, FLNC, RBM20, PLN and DSP, heart failure predominance in BAG3 and an on average more favourable course in A-band TTNtv, with the exception of M-band truncations [5, 25, 36]. In patients with LMNA, the disease progresses with high frequency over seven years, regardless of the initial phenotype [42]. AF, more frequent in LMNA, is associated with a worse prognosis in all genotypes [38]. The French PNDS brings together three comparisons with other causes of DCM [15]. In a cohort of 105 patients with DCM, by 45 years of age 55% of LMNA carriers had died of a cardiovascular cause or received a transplant, versus 11% of non-carriers. In 487 patients with DCM, testing was positive in 37% (43% in familial forms), and LMNA and the desmosomal genes concentrated the highest risk of sudden death and severe ventricular arrhythmia, regardless of LVEF. In a meta-analysis of about 8,000 patients, LMNA had the highest rates of transplantation and of sudden death or ventricular arrhythmia, particularly compared with the sarcomeric genes. In the French national registry, malignant arrhythmias occur in about 4% of patients per year, which requires periodic reassessment of the risk of sudden death and of the ICD indication [15].

Surveillance should include signs of progression that change stratification: onset of AV block, NSVT, fall in LVEF, new late gadolinium enhancement and AF [38, 40, 44]. In PLN p.(Arg14del) carriers, the phenotype may appear from adolescence to old age, which justifies lifelong follow-up [41]. In patients with recovered LVEF, therapy should be maintained, given the risk of relapse documented in TRED-HF [58, 83]. Periodic reassessment of variant classification and reanalysis of negative results are part of follow-up, particularly after the 2026 ClinGen update [5, 10]. Patients with neuromuscular disease and cardiac involvement should be followed by teams integrating cardiology and neurology [35]. For LMNA, intervals differ between documents. The French PNDS provides for annual assessment with Holter and CMR every 3–5 years, GeneReviews for assessment every 1–2 years in the asymptomatic carrier and ESC 2023 for ECG and echocardiogram every 1–3 years up to 60 years of age, with CMR every 2–5 years. In minors, the PNDS starts at 10 years of age, whereas HFSA 2018 defines intervals from birth for relatives without an informative test. Follow-up of pacemakers and ICDs takes place in a specialised setting. The PNDS also provides for psychological support and the involvement of school health services (personalised schooling plan) and occupational medicine [4, 6, 12, 15].

12. Summary and Final Considerations

Familial DCM comprises monogenic/oligogenic disorders modulated by age, sex and environment, sharing LV dilatation/dysfunction. Familial screening identifies disease in approximately 30% of idiopathic DCM, and targeted testing identifies P/LP in approximately one-fifth of all DCM and up to half of familial forms [5, 22]. TTN, LMNA, MYH7, FLNC, BAG3, TNNT2, RBM20, SCN5A, DES, PLN, TNNC1 and DSP have the strongest evidence, with ClinGen 2026 expanding to 35 high-evidence curations [9, 10].

Genotype has practical consequences. In LMNA, truncating FLNC, PLN p.(Arg14del), RBM20 and DSP, sudden death may precede severe dysfunction, which justifies stratification with specific calculators and ICD indication above the usual LVEF thresholds, with formulations that differ between documents: ESC 2022 uses LVEF <50% with two or more factors and, for LMNA, a 5-year risk ≥10%; ESC 2023 applies the recommendation to LVEF >35% with gene-specific additional factors and shared decision-making; HRS 2019 uses LVEF <45% by gene [4, 12, 44, 48, 54]. The 2022 French PNDS combines the four-factor rule with the calculator and the 10% threshold, prefers the transvenous ICD to the pacemaker when pacing is indicated and anticoagulates all AF regardless of the risk score [15]. TTNtv, the most frequent, usually behave as a predisposition sensitive to triggers — alcohol, chemotherapy, pregnancy, inflammation — and on average respond well to treatment, but M-band location is associated with high arrhythmic risk [25–28].

Pharmacotherapy is HF treatment extrapolated from unstratified trials; published genotype-specific trials were negative (REALM-DCM) or inconclusive (i-PHORECAST). Development centres on BAG3/LMNA gene therapies, a PLN p.(Arg14del) medicine and cardiac myosin activation for MYH7/TTN DCM, all without published efficacy results [85, 87, 89–93]. Non-European database under-representation reduces diagnostic value [102].

Core geneticist tasks are extended pedigrees, testing the most informative relative with high-evidence genes, phenotype-contextual interpretation, cascade testing only for P/LP, clinical screening when uninformative, preconception reproductive discussion and periodic variant reassessment [2, 5, 12].

13. References

1. Cowan JR, van Spaendonck-Zwarts KY, Hershberger RE. Dilated Cardiomyopathy. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 77–97. doi:10.1007/978-3-030-45457-9_5.
2. Hershberger RE, Jordan E. Dilated Cardiomyopathy Overview. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Created on 27 Jul 2007; updated on 29 Jul 2021; reviewed on 12 Dec 2024. NBK1309. PMID:20301486.
3. Orphanet. Familial isolated dilated cardiomyopathy. ORPHA:154. Validated epidemiological data (Orphadata, 23 Jun 2026). Disease entry. Accessed on 6 Oct 2026.
4. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–626. doi:10.1093/eurheartj/ehad194. PMID:37622657.
5. Verdonschot JAJ, van Spaendonck-Zwarts KY, Hellebrekers DMEI, Asselbergs FW, Behr ER, Charron P, et al. Genetic counselling implementation in dilated cardiomyopathy. A clinical consensus statement of the Heart Failure Association of the ESC, the ESC Working Group on Myocardial and Pericardial Diseases, and the ESC Council on Cardiovascular Genomics. Eur Heart J. 2026;47(24):3040–51. doi:10.1093/eurheartj/ehag159. PMID:41858107.
6. Hershberger RE, Jordan E. LMNA-Related Dilated Cardiomyopathy. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Created on 12 Jun 2008; updated on 17 Mar 2022. NBK1674.
7. GeneGuidance. Gene-specific clinical curation (TTN, LMNA, MYH7, BAG3, FLNC, RBM20, DSP, TNNT2, PLN, DES, SCN5A, TNNC1) and conditions ORPHA:154 and ORPHA:436242. Local database, version of 26 Sep 2026; includes ClinGen Actionability AC138 and Asatryan B et al., Natural history, phenotype spectrum, and clinical outcomes of desmin (DES)-associated cardiomyopathy, Circ Genom Precis Med 2025;18(2):e004878 (PMID:39968648).
8. Firth HV, Hurst JA. Dilated cardiomyopathy (DCM). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 394–7.
9. Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L, Brown E, et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation. 2021;144(1):7–19. doi:10.1161/CIRCULATIONAHA.120.053033. PMID:33947203.
10. Jordan E, Grover P, Parker P, Cowan J, Asatryan B, Ai T, et al. An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy. Circulation. 2026 Sep 8 [advance electronic publication]. doi:10.1161/CIRCULATIONAHA.126.080302. PMID:42708185.
11. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10(9):531–47. doi:10.1038/nrcardio.2013.105. PMID:23900355.
12. Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, et al. Genetic Evaluation of Cardiomyopathy — A Heart Failure Society of America Practice Guideline. J Card Fail. 2018;24(5):281–302. doi:10.1016/j.cardfail.2018.03.004. PMID:29567486.
13. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Prise en charge d’une mort subite du sujet jeune. Centre de référence pour la prise en charge des maladies rythmiques héréditaires de l’Ouest, CHU de Nantes; filière CARDIOGEN. Version de septembre 2022. Saint-Denis La Plaine: HAS; 28 Oct 2022. HAS page.
14. Groeneweg JA, van Dalen BM, Cox MPGJ, Heymans S, Braam RL, Michels M, et al. 2023 European Society of Cardiology guidelines on the management of cardiomyopathies: Statement of endorsement by the NVVC. Neth Heart J. 2025;33(5):148–56. doi:10.1007/s12471-025-01955-2. PMID:40227490.
15. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Laminopathies avec présentation cardiaque. Centre de référence des maladies cardiaques héréditaires ou rares; Centre de référence des maladies neuromusculaires Nord/Est/Ile de France; Filière nationale de santé CARDIOGEN. Version du 21 octobre 2022. Saint-Denis La Plaine: HAS; 13 Dec 2022. HAS page.
16. Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Böhm M, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37(23):1850–8. doi:10.1093/eurheartj/ehv727. PMID:26792875.
17. Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. 1992;326(2):77–82. doi:10.1056/NEJM199201093260201. PMID:1727235.
18. Mestroni L, Maisch B, McKenna WJ, Schwartz K, Charron P, Rocco C, et al. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J. 1999;20(2):93–102. doi:10.1053/euhj.1998.1145. PMID:10099905.
19. van der Zwaag PA, van den Berg MP. Introduction to Hereditary Cardiomyopathies. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 57–60. doi:10.1007/978-3-030-45457-9_3.
20. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 1999;341(23):1715–24. doi:10.1056/NEJM199912023412302. PMID:10580070.
21. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–28. doi:10.1056/NEJMoa1110186. PMID:22335739.
22. Huggins GS, Kinnamon DD, Haas GJ, Jordan E, Hofmeyer M, Kransdorf E, et al. Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy. JAMA. 2022;327(5):454–63. doi:10.1001/jama.2021.24674. PMID:35103767.
23. National Center for Biotechnology Information; EMBL-EBI. MANE (Matched Annotation from NCBI and EMBL-EBI) Select and Plus Clinical, release v1.5 (GRCh38). Summary file. Accessed on 6 Oct 2026.
24. Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7(270):270ra6. doi:10.1126/scitranslmed.3010134. PMID:25589632.
25. Perotto M, Radesich C, Paldino A, Gandin I, Verdonschot JAJ, Kim Y, et al. Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry. Circ Genom Precis Med. 2026 Jul 8:e005422. doi:10.1161/CIRCGEN.125.005422. PMID:42417033.
26. Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchía J, et al. Genetic Etiology for Alcohol-Induced Cardiac Toxicity. J Am Coll Cardiol. 2018;71(20):2293–302. doi:10.1016/j.jacc.2018.03.462. PMID:29773157.
27. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, et al. Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Circulation. 2019;140(1):31–41. doi:10.1161/CIRCULATIONAHA.118.037934. PMID:30987448.
28. Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, et al. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. N Engl J Med. 2016;374(3):233–41. doi:10.1056/NEJMoa1505517. PMID:26735901.
29. National Center for Biotechnology Information. ClinVar: records VCV000002162192 (LMNA c.364A>T), VCV000044580 (PLN p.Arg14del), VCV000044260 (DES c.38C>T), VCV000005981 (BAG3 c.626C>T), VCV000043980 and VCV000000271 (RBM20 p.Arg636), VCV000014500 (LMNA c.1824C>T). ClinVar. Accessed on 6 Oct 2026.
30. Domínguez F, Cuenca S, Bilińska Z, Toro R, Villard E, Barriales-Villa R, et al. Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations. J Am Coll Cardiol. 2018;72(20):2471–81. doi:10.1016/j.jacc.2018.08.2181. PMID:30442290.
31. Ortiz-Genga MF, Cuenca S, Dal Ferro M, Zorio E, Salgado-Aranda R, Climent V, et al. Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. J Am Coll Cardiol. 2016;68(22):2440–51. doi:10.1016/j.jacc.2016.09.927. PMID:27908349.
32. Smith ED, Lakdawala NK, Papoutsidakis N, Aubert G, Mazzanti A, McCanta AC, et al. Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. 2020;141(23):1872–84. doi:10.1161/CIRCULATIONAHA.119.044934. PMID:32372669.
33. van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14(11):1199–207. doi:10.1093/eurjhf/hfs119. PMID:22820313.
34. Tadros R, Cadrin-Tourigny J. Hereditary Cardiac Conduction Diseases. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 273–85. doi:10.1007/978-3-030-45457-9_17.
35. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 371–85. doi:10.1007/978-3-030-45457-9_22.
36. Escobar-Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, Navarro M, Gallego-Delgado M, et al. Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy. J Am Coll Cardiol. 2021;78(17):1682–99. doi:10.1016/j.jacc.2021.08.039. PMID:34674813.
37. Stroeks SLVM, Bart NK, Rossano J, Claggett B, Beelen NJ, Buchan RJ, et al. Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum: Insights From the SHaRe Registry. J Am Coll Cardiol. 2026;87(25):3573–88. doi:10.1016/j.jacc.2026.03.054. PMID:42159538.
38. Balakrishnan ID, Heymans ABM, Claggett B, Stewart GC, Seidman CE, Stroeks SLVM, et al. Atrial Fibrillation in Genotyped Dilated Cardiomyopathy: Epidemiology, Risk Factors, and Outcomes: Insights From the SHaRe Registry. Circ Heart Fail. 2026 Sep 10:e014322. doi:10.1161/CIRCHEARTFAILURE.125.014322. PMID:42717878.
39. Brodt C, Siegfried JD, Hofmeyer M, Martel J, Rampersaud E, Li D, et al. Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Card Fail. 2013;19(4):233–9. doi:10.1016/j.cardfail.2013.03.001. PMID:23582089.
40. Gigli M, Stolfo D, Barbati G, Graw S, Chen SN, Merlo M, et al.; Filamin C Registry Consortium. Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants. JAMA Cardiol. 2025;10(4):359–69. doi:10.1001/jamacardio.2024.5543. PMID:39937464.
41. Verstraelen TE, van Lint FHM, de Brouwer R, Proost VM, van Drie E, Bosman LP, et al. Age-related penetrance of phospholamban p.Arg14del cardiomyopathy. Eur J Heart Fail. 2025;27(12):3269–77. doi:10.1002/ejhf.3672. PMID:40264254.
42. Kumar S, Baldinger SH, Gandjbakhch E, Maury P, Sellal JM, Androulakis AF, et al. Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers. J Am Coll Cardiol. 2016;68(21):2299–307. doi:10.1016/j.jacc.2016.08.058. PMID:27884249.
43. van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ, et al. Risk factors for malignant ventricular arrhythmias in lamin A/C mutation carriers: a European cohort study. J Am Coll Cardiol. 2012;59(5):493–500. doi:10.1016/j.jacc.2011.08.078. PMID:22281253.
44. Wahbi K, Ben Yaou R, Gandjbakhch E, Anselme F, Gossios T, Lakdawala NK, et al. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies. Circulation. 2019;140(4):293–302. doi:10.1161/CIRCULATIONAHA.118.039410. PMID:31155932.
45. Escobar-Lopez L, Ochoa JP, Royuela A, Verdonschot JAJ, Dal Ferro M, Espinosa MA, et al. Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol. 2022;80(12):1115–26. doi:10.1016/j.jacc.2022.06.040. PMID:36109106.
46. Rushakoff JA, Flores Rosario K, Grover P, Wang A. Smartwatch bradycardia alarms leading to a diagnosis of lamin A/C cardiomyopathy: a case report. Eur Heart J Case Rep. 2025;9(9):ytaf415. doi:10.1093/ehjcr/ytaf415. PMID:40918212. Full text PMC12412439.
47. Firth HV, Hurst JA. Cardiomyopathy in children under 10 years. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 84–7.
48. Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi:10.1093/eurheartj/ehac262. PMID:36017572.
49. Ramos-López N, Mora-Ayestarán N, Ochoa JP, Claver E, Gómez González C, Poel E, et al. Arrhythmic Risk Stratification According to LGE Corridors and Genetics in Nonischemic Dilated Cardiomyopathy. Circulation. 2026 Sep 8 [advance electronic publication]. doi:10.1161/CIRCULATIONAHA.126.080608. PMID:42708210.
50. Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20(9):899–909. doi:10.1038/s41436-018-0039-z. PMID:29904160.
51. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726. doi:10.1093/eurheartj/ehab368. PMID:34447992.
52. Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24(8):1307–67. doi:10.1093/europace/euac030. PMID:35373836. PMCID:PMC9435643.
53. Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenperä P, et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015;36(34):2327–37. doi:10.1093/eurheartj/ehv253. PMID:26084686.
54. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16(11):e301–72. doi:10.1016/j.hrthm.2019.05.007. PMID:31078652.
55. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.4.8 and 1.4.8.2, Tables 1.11–1.12. doi:10.1007/978-3-662-63123-2_1.
56. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627–39. doi:10.1093/eurheartj/ehad195. PMID:37622666.
57. van Essen BJ, Ceelen DCH, Ouwerkerk W, Teng TK, Tharshana GN, Hew FM, et al. Pharmacologic Treatment of Heart Failure With Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis. J Am Coll Cardiol. 2025;86(24):2513–26. doi:10.1016/j.jacc.2025.08.054. PMID:40892608.
58. Boslough M, Taylor MRG, Mestroni L, Lombardi R. Genetic Dilated Cardiomyopathy: A Review. Methodist Debakey Cardiovasc J. 2026;22(4):68–77. doi:10.14797/mdcvj.1849. PMID:42761961.
59. Sletten Olsen PA, Leren IS, Lie ØH, Bugge C, Beitnes JO, Berge KE, et al. Cardiac Function and the Effect of Heart Failure Treatment in Patients With Genotype-Positive Dilated Cardiomyopathy. JACC Heart Fail. 2026 Aug 28:103367. doi:10.1016/j.jchf.2026.103367. PMID:42670740.
60. U.S. Food and Drug Administration. ENTRESTO (sacubitril and valsartan) tablets; ENTRESTO SPRINKLE. Prescribing information, version effective on 6 Jul 2026 (NDA 207620, 218591). DailyMed.
61. European Medicines Agency. Entresto (sacubitril/valsartan): EPAR — Summary of Product Characteristics (Portuguese). EPAR. Accessed on 6 Oct 2026.
62. U.S. Food and Drug Administration. VASOTEC (enalapril maleate) tablets. Prescribing information, version effective on 23 Jan 2026 (NDA 018998). DailyMed.
63. U.S. Food and Drug Administration. DIOVAN (valsartan) tablets. Prescribing information, version effective on 11 Aug 2026 (NDA 021283). DailyMed.
64. U.S. Food and Drug Administration. COREG (carvedilol) tablets. Prescribing information, version effective on 31 Jul 2026 (NDA 020297). DailyMed.
65. U.S. Food and Drug Administration. TOPROL-XL (metoprolol succinate) extended-release tablets. Prescribing information, version effective on 3 Mar 2026 (NDA 019962). DailyMed.
66. U.S. Food and Drug Administration. ALDACTONE (spironolactone) tablets. Prescribing information, version effective on 28 Nov 2025 (NDA 012151). DailyMed.
67. U.S. Food and Drug Administration. INSPRA (eplerenone) tablets. Prescribing information, version effective on 23 Jun 2025 (NDA 021437). DailyMed.
68. INFARMED. Inspra (eplerenone) 25 mg and 50 mg film-coated tablets — Summary of Product Characteristics [Internet]. Lisbon: INFARMED, I.P.; marketing authorisation holder Viatris Healthcare, Lda. (Infomed med_id 38306). https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=38306&tipo_doc=rcm (accessed on 26 Oct 2026)
69. U.S. Food and Drug Administration. FARXIGA (dapagliflozin) tablets. Prescribing information, version effective on 10 Jul 2026 (NDA 202293). DailyMed.
70. European Medicines Agency. Forxiga (dapagliflozin): EPAR — Summary of Product Characteristics (Portuguese). EPAR. Accessed on 6 Oct 2026.
71. U.S. Food and Drug Administration. JARDIANCE (empagliflozin) tablets. Prescribing information (openFDA entry, NDA 204629). DailyMed.
72. European Medicines Agency. Jardiance (empagliflozin): EPAR — Summary of Product Characteristics (Portuguese). EPAR. Accessed on 6 Oct 2026.
73. U.S. Food and Drug Administration. CORLANOR (ivabradine) tablets and oral solution. Prescribing information, version effective on 10 Nov 2025 (NDA 206143, 209964). DailyMed.
74. European Medicines Agency. Procoralan (ivabradine): EPAR — Summary of Product Characteristics (Portuguese). EPAR. Accessed on 6 Oct 2026.
75. U.S. Food and Drug Administration. VERQUVO (vericiguat) tablets. Prescribing information, version effective on 21 Jan 2026 (NDA 214377). DailyMed.
76. European Medicines Agency. Verquvo (vericiguat): EPAR — Summary of Product Characteristics (Portuguese). EPAR. Accessed on 6 Oct 2026.
77. U.S. Food and Drug Administration. Drugs@FDA: NDA submission history for 207620, 218591, 202293, 204629, 214377, 206143 and 209964. Drugs@FDA. Accessed on 6 Oct 2026.
78. European Medicines Agency. Medicines data (human medicines report, 6 Oct 2026): authorisation dates of Entresto, Neparvis, Forxiga, Jardiance, Verquvo, Procoralan and Corlentor. EMA — download medicine data. Accessed on 6 Oct 2026.
79. Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med. 2016;375(13):1221–30. doi:10.1056/NEJMoa1608029. PMID:27571011.
80. Tetaj N, Segreti A, Ferro A, Ligorio V, Spagnolo A, Grigioni F. High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN and Desmosomal Genes in the ESC 2023 Era. Genes (Basel). 2026;17(4):370. doi:10.3390/genes17040370. PMID:42074488.
81. Anselme F, Moubarak G, Savouré A, Godin B, Borz B, Drouin-Garraud V, Gay A. Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders. Heart Rhythm. 2013;10(10):1492–8. doi:10.1016/j.hrthm.2013.06.020. PMID:23811080.
82. Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393(10166):61–73. doi:10.1016/S0140-6736(18)32484-X. PMID:30429050.
83. Cheng L, Hammersley D, Ragavan A, Javed S, Mukhopadhyay S, Gregson J, et al. Long-term follow-up of the TRED-HF trial: Implications for therapy in patients with dilated cardiomyopathy and heart failure remission. Eur J Heart Fail. 2025;27(1):113–23. doi:10.1002/ejhf.3475. PMID:39349993.
84. U.S. Food and Drug Administration. Metformin hydrochloride tablets, USP — prescribing information (sections 2.1–2.3). DailyMed setid 011de1a5-1ac0-4831-9e8d-26ec79ba2205; revised 21 Aug 2024. DailyMed. Accessed on 2 Nov 2026.
85. Garcia-Pavia P, Palomares JFR, Sinagra G, Barriales-Villa R, Lakdawala NK, Gottlieb RL, et al. REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy. Circ Heart Fail. 2024;17(7):e011548. doi:10.1161/CIRCHEARTFAILURE.123.011548. PMID:38979608.
86. Lakdawala NK, Hershberger RE, Garcia-Pavia P, Elliott PM, Ginns J, Meder B, et al. Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy: A Phase 2 Open-Label Trial. J Am Coll Cardiol. 2025;86(25):2598–612. doi:10.1016/j.jacc.2025.09.1511. PMID:41217321.
87. de Brouwer R, Te Rijdt WP, Hoorntje ET, Amin A, Asselbergs FW, Cox MGPJ, et al. A randomized controlled trial of eplerenone in asymptomatic phospholamban p.Arg14del carriers. Eur Heart J. 2023;44(40):4284–7. doi:10.1093/eurheartj/ehad292. PMID:37210081.
88. Butler J, McMullan CJ, Anstrom KJ, Barash I, Bonaca MP, Borentain M, et al. Vericiguat in patients with chronic heart failure and reduced ejection fraction (VICTOR): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2025;406(10510):1341–50. doi:10.1016/S0140-6736(25)01665-4. PMID:40897189.
89. Nuevocor. A Study With NVC-001 in Patients With LMNA-related Dilated Cardiomyopathy (SUNBEAM-LMNA). ClinicalTrials.gov NCT07606274. Accessed on 6 Oct 2026.
90. Alexion Pharmaceuticals. ALXN2350 in Adult Participants With BAG3-Associated Dilated Cardiomyopathy. ClinicalTrials.gov NCT07218887. Accessed on 6 Oct 2026.
91. Rocket Pharmaceuticals. A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in BAG3-associated DCM. ClinicalTrials.gov NCT07137338. Accessed on 6 Oct 2026.
92. AstraZeneca. A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy. ClinicalTrials.gov NCT07241104. Accessed on 6 Oct 2026.
93. Kardigan. A Study of the Efficacy and Safety of Danicamtiv in Participants With Symptomatic Genetic and Familial Dilated Cardiomyopathy (DAN-301) and open-label extension. ClinicalTrials.gov NCT07210723 and NCT07771465. Accessed on 6 Oct 2026.
94. Avendaño Solá C (sponsor). Early Treatment With Candesartan vs Placebo in Asymptomatic Genetic Carriers of Dilated Cardiomyopathy (EARLY-GENE). ClinicalTrials.gov NCT05321875. Accessed on 6 Oct 2026.
95. CIBER. Study of Personalized Allocation of Defibrillators in Non-ischemic Heart Failure (SPANISH-1). ClinicalTrials.gov NCT06055504. Accessed on 6 Oct 2026.
96. Institut National de la Santé et de la Recherche Médicale. Preventive Effect of ACE Inhibitor Perindopril on the Onset or Progression of Left Ventricular Dysfunction in Subjects at a Preclinical Stage From Families With Dilated Cardiomyopathy. ClinicalTrials.gov NCT01583114. Accessed on 6 Oct 2026.
97. Muller SA, Beelen NJ, Paldino A, Gonzalez-Maniega C, Bundgaard H, Christensen AH, et al. Optimizing Screening Intervals for At-Risk Relatives of Dilated Cardiomyopathy Carrying a TTNtv. Circ Heart Fail. 2026 Sep 21:e013822. doi:10.1161/CIRCHEARTFAILURE.125.013822. PMID:42765307.
98. Kransdorf EP, Jain R, Mead JO, Haas G, Hofmeyer M, Ewald GA, et al. Evaluation of Women With Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study. Circ Genom Precis Med. 2026;19(2):e005541. doi:10.1161/CIRCGEN.125.005541. PMID:41878807.
99. Nannenberg EA, Arens Y. Prenatal Diagnosis and Preimplantation Genetic Testing for Inherited Cardiac Diseases. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 457–61. doi:10.1007/978-3-030-45457-9_27.
100. De Backer J, Haugaa KH, Hasselberg NE, de Hosson M, Brida M, Castelletti S, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462–568. doi:10.1093/eurheartj/ehaf193. PMID:40878294.
101. Codd MB, Sugrue DD, Gersh BJ, Melton LJ 3rd. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation. 1989;80(3):564–72. doi:10.1161/01.cir.80.3.564. PMID:2766509.
102. Jordan E, Kinnamon DD, Haas GJ, Hofmeyer M, Kransdorf E, Ewald GA, et al. Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry. JAMA. 2023;330(5):432–41. doi:10.1001/jama.2023.11970. PMID:37526719.
103. Ribeiro EM, coordinator. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 163–4.