1q21.1 Deletion and Duplication

Class of recurrent copy number variants (CNVs) of band 1q21.1, generated by non-allelic homologous recombination between segmental duplications: reciprocal deletion and duplication of the distal region (BP3–BP4, "class I"), extended BP1/BP2–BP4 CNVs ("class II") and deletion and duplication of the proximal region (BP2–BP3, the TAR syndrome region); neurodevelopmental susceptibility loci with incomplete penetrance and variable expressivity.

Literature and regulatory information updated: 18 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Common syndromic description

Recurrent 1q21.1 CNVs do not form a clinically recognisable syndrome in the classical sense. They form a set of dosage alterations, mediated by the same genomic architecture, that increase the risk of neurodevelopmental disorders, congenital anomalies and psychiatric disease without determining them. Some carriers have no findings at all. Others present, in variable combinations, mild and non-specific facial dysmorphism, mild to moderate developmental delay, learning difficulties or mild ID, altered head circumference, ocular anomalies, congenital heart disease, genitourinary and skeletal anomalies, seizures, ASD, ADHD, anxiety and mood disorders and, in adulthood, schizophrenia [1, 2, 4]. Transmission from parents with a normal or mild phenotype is the rule, which made these CNVs the model of the so-called "neurodevelopmental susceptibility loci": the alteration is pathogenic and contributes to the phenotype, but other genetic and environmental factors determine whether and how it manifests [1, 32]. The feature that distinguishes the distal region from other recurrent CNVs is the mirror effect on head and brain size: the deletion is associated with microcephaly and the duplication with macrocephaly [8, 33].

1.2. Founding articles and historical milestones

In 2004, Christiansen and colleagues, in a series of 505 patients with congenital heart disease screened by quantitative PCR of GJA5, described three contiguous gene deletions of 1q21.1 encompassing ACP6, GJA5 and GJA8, all with aortic arch obstruction and without consistent dysmorphism, absent in 520 controls; one carrier parent was apparently unaffected [34]. In 2008, two studies delineated the distal CNVs as paediatric genomic disorders. Mefford and colleagues (New England Journal of Medicine) found the 1.35 Mb deletion in 25 of 5218 patients with unexplained ID, autism or congenital anomalies and in none of 4737 controls, and the reciprocal duplication in 9 patients and one control, with variable paediatric phenotypes and frequent inheritance from mildly affected or unaffected parents [18]. Brunetti-Pierri and colleagues (Nature Genetics), using 16,557 samples from Texas Children's Hospital and Baylor College of Medicine, showed that the deletion is associated with microcephaly and the duplication with macrocephaly, and defined classes I (distal region only) and II (larger deletions including the TAR region) [8]. In the same year, the International Schizophrenia Consortium, Stefansson and colleagues and Walsh and colleagues identified the 1q21.1 deletion among the first CNVs associated with schizophrenia [35–37]. OMIM created entries #612474 and #612475 on 12 December 2008 [3, 5]. In 2012, Rosenfeld and colleagues characterised the deletions and duplications limited to the proximal region and the combined proximal and distal deletions [7]; Soemedi and colleagues demonstrated cardiac phenotypic specificity (duplication and tetralogy of Fallot; deletion and other heart defects) [24]. These were followed by the penetrance estimates of Rosenfeld (2013) [23], the studies of unascertained carriers in the UK Biobank [21, 38], the ENIGMA-CNV imaging cohort [33] and the recalculation of penetrance for ID by Goh and colleagues, published online in October 2025 and in the 2026 volume of the European Journal of Human Genetics [10].

1.3. Current nomenclature and classifications

Band 1q21.1 contains four large blocks of segmental duplications in direct orientation, designated BP1 to BP4 by Mefford and colleagues, which act as recombination hotspots [1, 18]. Three designation systems coexist and should be read together (Table 1). The first is the topographic division into the distal region (BP3–BP4) and the proximal region (BP2–BP3, which contains RBM8A, the TAR syndrome gene). The second is the Brunetti-Pierri classification: class I for CNVs limited to the distal region and class II for larger CNVs, of ~2 Mb, that include the proximal and distal regions [1, 8]. The third is the dosage curation of ClinGen (Clinical Genome Resource), which defines two regions: the distal one (ISCA-37421), which includes class II CNVs because it considers them "functionally similar" to BP3–BP4, and the proximal one (ISCA-37428), which spans BP1 or BP2 to BP3 and considers class II CNVs "functionally different" from those limited to the proximal region [6, 9]. Size designations have varied with platforms and genome assemblies: 1.35 Mb (Mefford, including the flanking segmental duplications), 1.2 Mb and ~0.8 Mb (unique sequence between the breakpoints, ClinGen minimal coordinates). GeneReviews considers them the same clinical entity [1]. Titles have also changed: the GeneReviews chapter went from "1q21.1 Recurrent Microdeletion" to "1q21.1 Recurrent Deletion" in the 2024 update [1], and Orphanet retains "1q21.1 microdeletion syndrome" and "1q21.1 microduplication syndrome" [2, 4].

1.4. Scope of the article and types in the class

This article covers the distal deletions and duplications (the core of the class), class II CNVs and the proximal duplication. The proximal deletion only has an established phenotype when it is combined with a hypomorphic RBM8A allele in trans, causing TAR syndrome; here it appears only for differential diagnosis and counselling [6, 39, 40]. The 1q21.1 triplications, described in two probands of the French series of Bourgois, share the neurodevelopmental disorders of the deletions and duplications [15].

Table 1. Types of recurrent 1q21.1 CNVs.

2. Molecular Genetics and Pathophysiology

2.1. Genomic architecture and mechanism of formation

Band 1q21.1 is one of the most structurally complex regions of the human genome. Of its 5.4 Mb, only 25% is unique sequence; the rest corresponds to at least four large blocks of segmental duplications (270 kb to 2.2 Mb), mostly copy-number polymorphic, an inversion polymorphism spanning the recurrent region and, in the NCBI build 36 assembly, 15 gaps totalling ~700 kb [18]. As in the 22q11.2, 7q11.23, 15q11q13, 15q13.3, 16p11.2 and 17q21.31 regions, the flanking segmental duplications are in direct orientation and have high homology, which predisposes to misalignment in meiosis and to non-allelic homologous recombination (NAHR). The reciprocal product of each event is a deletion and a duplication of the intervening unique sequence [1, 9]. The Oxford Desk Reference describes the same mechanism as recombination between low copy repeats (LCRs) [32]. The duplication is detected less often than the deletion in clinical series, which is compatible with higher NAHR deletion rates than duplication rates in the male germline and with the better clinical tolerance of partial trisomies [18, 32].

Coordinates vary with the assembly and must not be converted by hand. For the distal region, the sources read give NCBI35 143.65–145 Mb and NCBI36 145.0–146.35 Mb (Mefford and OMIM), GRCh37 chr1:146,577,486–147,394,506 and GRCh38 chr1:147,105,904–147,917,509 (ClinGen) [3, 9, 18]. For the proximal region, hg18 144.0–144.5 Mb (Rosenfeld 2013), GRCh37 chr1:145,386,507–145,748,064 (ClinGen) or 145,394,956–145,762,959 (Levy 2023) and GRCh38 chr1:145,686,999–146,048,495 (ClinGen) [6, 16, 23]. The size calculated in a report depends on probe density and on whether the segmental duplications are included; a CNV significantly larger or smaller than the recurrent interval may be clinically distinct and should not be equated with the class without analysis [1].

2.2. Genes of the distal region

ClinGen stresses that the genes used as landmarks "are not necessarily causal of the phenotype", and GeneReviews states that no single gene explains the overall phenotype; haploinsufficiency or excess dosage of several genes probably contributes to the phenotypes associated with each of them (Table 2) [1, 9]. Mefford and colleagues sequenced the remaining GJA5 and GJA8 alleles in deletion carriers without finding variants and detected no differences in epigenetic marks between affected and unaffected carriers [3, 18].

Table 2. Genes of the distal 1q21.1 region and their relationship with the phenotype.

2.3. The mirror effect on brain size

In 2008, Brunetti-Pierri and colleagues proposed that HYDIN2, a paralogue inserted into 1q21.1 by interchromosomal duplication from 16q22.2 during primate evolution and absent from the reference assembly of the time, was the dosage-sensitive gene responsible for the microcephaly and macrocephaly, because it was deleted or duplicated in all cases and shares the ASH domain with ASPM, a primary microcephaly gene [8]. Dumas and colleagues studied 42 individuals with 1q21-associated micro- or macrocephaly by targeted comparative genomic hybridisation and found, among 53 genes, the strongest association with brain size in the genes with DUF1220 sequences (NBPF family), with a correlation between copy number and head circumference Z in the deletion group and, in a population without disease, with grey matter volume [3, 47]. Lemée and colleagues (Nucleic Acids Research, September 2025) overexpressed the eight human coding genes of the distal region in zebrafish: only CHD1L produced macrocephaly and greater larval length, and deletion of chd1l produced the opposite phenotype; the mirror phenotypes were repeated in mouse embryos. In neural progenitors derived from induced pluripotent stem cells (iPSCs) lacking CHD1L, the gene regulated the expression and chromatin accessibility of genes of neuronal differentiation and synaptogenesis, including autism genes, by facilitating access of SOX2 and OTX2 and compacting chromatin through the NuRD complex; the authors propose CHD1L as a determinant of the head circumference and growth phenotypes [44]. The three hypotheses are not mutually exclusive and none has been tested in humans with intragenic variants.

In humans, the structural correlate is quantified in the ENIGMA-CNV consortium with the UK Biobank (28 deletion carriers, 22 duplication carriers and 37,088 non-carriers, 15 magnetic resonance imaging sites): there is a positive dosage effect on intracranial volume (β 1.47; p=2.8×10⁻²⁵) and cortical surface area (β 0.81), most marked in the frontal and cingulate cortices, and a negative effect on the caudate nucleus and hippocampus. The deletion reduces intracranial volume by 17% (Cohen's d −1.84) and cortical area by 23%; the duplication increases intracranial volume by 10% (d +0.90) and reduces the caudate (−16%) and hippocampus (−15%); an Icelandic sample replicated the results [33].

2.4. Cellular mechanisms and models

iPSC-derived neurons from deletion or duplication carriers have altered morphology, dysregulated synaptic density and cortical layer identity, and differential expression of calcium channels, which suggests the activity of these channels as a potential pharmacological target [48]. In carrier lymphoblastoid lines, CHD1L and PRKAB2 proteins are reduced, with chromatin remodelling defects and lower AMPK function [45]. The mouse model of the deletion has shorter head-to-tail length, altered mesolimbic dopaminergic transmission and an increased response to psychostimulants [49]. Isogenic models in human embryonic stem cells (hESCs) edited by CRISPR/Cas9 reproduce the reciprocal size of neural progenitor spheroids, with more GABAergic components in the deletion and a more proliferative state in the duplication [50]; meta-analysis of the single-cell transcriptome of these models shows directional enrichment of ASD, bipolar disorder and schizophrenia genes and points to BPTF (NURF complex) as a potential target [51]. iPSC-derived microglia with the deletion or duplication have an aberrant inflammatory response [52]. The review by Yoon and Mao brings these mechanisms together [53].

2.5. Proximal region and relationship with TAR syndrome

The proximal BP2–BP3 region contains RBM8A, which encodes the Y14 protein of the exon junction complex. TAR syndrome results from the combination, in trans, of a null allele (almost always the proximal deletion) and a low-frequency regulatory hypomorphic allele of RBM8A; it was this architecture that explained the inheritance pattern that mimicked recessive inheritance with a microdeletion [39, 40]. The heterozygous proximal deletion without the second allele has an HI score of 0 in ClinGen: reports of carriers without TAR describe non-specific and sometimes contradictory neurodevelopmental phenotypes, the rarity of these phenotypes in TAR itself suggests ascertainment bias, most deletions are inherited from unaffected parents and case-control studies were excluded from scoring because they apparently included patients with TAR [6]. The proximal duplication has TS 1 [6]. Class II CNVs, which span both regions, carry the risk of TAR when the other chromosome has the hypomorphic RBM8A allele: in the Rosenfeld series, two patients with proximal and distal deletion had "partial" TAR [7].

2.6. Penetrance and expressivity

The penetrance of these CNVs depends on the outcome measured and the reference population, and the figures from the three main sources are not interchangeable (Table 3). Rosenfeld and colleagues (2013) compared the frequency in patients referred for postnatal array comparative genomic hybridisation (aCGH) with the frequency in controls and estimated the risk of any phenotype prompting the study, assuming a baseline risk of 5.08% [23, 32]. Kendall and colleagues (2019) recalculated penetrance for schizophrenia, ASD or ID with UK Biobank control frequencies [21]. Goh and colleagues (2026) proposed a new definition, the probability that the alteration causes the phenotype excluding the phenotype due to unrelated causes, and a formula that uses the prevalence of paediatric ID in high-income countries (1.1%) instead of 5.08%; the affected individuals came from eight pooled studies, mostly children with ID or developmental delay, and the controls from the 269,885 gnomAD v4.0 exomes [10]. This analysis follows a systematic review by the same authors of 83 recurrent CNVs, with nine pooled cohorts of affected individuals compared with gnomAD [54].

Table 3. Penetrance estimates by CNV type.

Sources: [6, 10, 21, 23, 32].

The reduction achieved by the new formula is about 5–10-fold for low-penetrance CNVs. The proximal duplication belongs to a group of four CNVs with ID penetrance of ~1% and a confidence interval that includes values ≤1%, but not 0%; together with seven CNVs with 0% and three with 1–3%, they form 14 CNVs "with penetrance close to 0%", present in ~2.7% of gnomAD controls. The authors call for conservative interpretation of these four, because ancestry and publication and selection biases may explain the small excess. The distal deletions and duplications are not in this group [10]. The authors themselves limit the scope of the figures: they are penetrances for ID, pleiotropy may give higher penetrances for other outcomes, ASD and schizophrenia cannot be estimated with these formulas, gnomAD controls may include people with ID, and the affected individuals were studied by microarray and the controls by exome. With a penetrance of 10% and a baseline risk of 5%, up to 30% of published cases may have incidental phenotypes due to ascertainment bias [10].

For other outcomes, penetrance can only be read from the data of each cohort. In the Simons VIP and Cardiff cohort studied by Linden, 61% of children with the distal deletion and 71% of children with the distal duplication had at least one psychiatric diagnosis, compared with about 11% of family controls [55]; the case-control associations with schizophrenia, ADHD and heart disease are in section 3. Expressivity is variable within the same family: siblings and cousins with the same deletion may be normal or mildly affected, and about 25% of transmitting parents have a normal phenotype, as in the 16p11.2 and 15q13.3 regions [1]. GeneReviews does not identify genotype-phenotype correlations within the recurrent deletion [1], and the Turkish cohort of Mutlucan Köseoğlu found no differences by inheritance, parental origin or size [56].

2.7. Modifiers and dual diagnoses

Dual molecular diagnoses, with pathogenic alterations at distinct loci, have been described in several carriers; they may explain severe or atypical phenotypes [1, 12, 15]. Qiao and colleagues sequenced the exome of two families (a deletion transmitted by the maternal grandmother and a paternal duplication) and found variants in SMPD1, WNK3 (X-linked, segregating with the phenotype and with the X-inactivation pattern), NOS1, ATF6 and EFHC1, stress-response genes that may act as "second hits" [57]. In a fetus with a familial 1q21.1 deletion, a concomitant CHD1L variant accompanied oligohydramnios and bilateral renal dysplasia [58]. A patient with long QT and a distal deletion also had a pathogenic variant in KCNH2 [1]. In the most extreme case of interaction within the region itself, a patient in the Brunetti-Pierri series had a distal duplication and a TAR deletion inherited from the mother, present in two equally affected siblings [8]. Parental origin does not appear to modify the severity of the deletion [1]; in the proximal duplication, Levy and colleagues observed maternal inheritance in the nine clinical cases with tested origin and proposed a greater impact in boys who inherit it from the mother, an observation from a small cohort without replication in the sources read [16].

2.8. CNV nomenclature and point variants of the genes of the region

The report should describe the CNV in International System for Human Cytogenomic Nomenclature (ISCN) notation with the assembly and coordinates, for example arr[GRCh37] 1q21.1q21.2(146542653_147828088)x3 mat for the maternally inherited duplication in the case in section 10 (notation built from the published coordinates) [11]. The point variants of GJA5 and GJA8 cited in the literature do not belong to the CNV, but they appear in the differential. Normalised in ClinVar on the MANE Select transcripts GJA5 NM_181703.4 (ENST00000579774.3) and GJA8 NM_005267.5 (ENST00000369235.2), both within the distal interval [59], they are: GJA5 NM_181703.4:c.286G>T p.(Ala96Ser), Gollob's variant in atrial fibrillation, now of uncertain significance (VariationID 16998); GJA8 NM_005267.5:c.137G>T p.(Gly46Val) and c.131T>C p.(Val44Ala), with conflicting classifications; and GJA8 c.827C>T p.(Ser276Phe), of uncertain significance [42, 60, 61]. In Gollob's original series, three of the four GJA5 variants in 15 patients with idiopathic atrial fibrillation were somatic (atrial tissue, absent from lymphocytes) [42, 61]. Most "pathogenic" ClinGen and ClinVar records involving GJA5 correspond to the multigenic 1q21.1 CNVs, whose phenotype belongs to the interval and not to the gene [42].

3. Clinical Spectrum and Manifestations by Organ System

Clinical data come from three types of cohorts, which measure different things. Series of probands referred for microarray because of delay, ID, autism or congenital anomalies describe the phenotype of those who reach the laboratory and overestimate severity. Family cohorts (Simons VIP, Cardiff) compare carriers with non-carrier relatives and reduce part of this bias. Population cohorts of unselected adults (UK Biobank, deCODE, iPSYCH) show the effect in people not ascertained by phenotype, with the opposite bias of healthy participation. None of the sources consulted separates natural history from the course under early intervention or treatment, because there is no specific treatment and the series do not describe the effect of supportive therapies.

3.1. Distal deletion: phenotype in clinical series

GeneReviews pools 102 probands from five series (Brunetti-Pierri 2008, Mefford 2008, Bernier 2016, Edwards 2021 and Bourgois 2023), not all assessed for each feature (Table 4) [1]. The individual series give different proportions because they differ in ascertainment and assessment method (Table 5).

Table 4. Frequency of features in the distal deletion, according to GeneReviews (102 probands).

Table 5. Series of distal deletion carriers.

Face and growth. The dysmorphism is mild, variable and not characteristic: frontal bossing, thin eyebrows, deep-set eyes, epicanthic folds, prominent or broad nasal root with a bulbous tip, long philtrum and high-arched palate [1]. Photographs from the Brunetti-Pierri series show, in probands and carrier parents, frontal bossing, deep-set eyes and a bulbous nose as the most frequent features [8]. Microcephaly is the most consistent sign. In 29 carriers (probands, parents and siblings) assessed by Brunetti-Pierri, the mean head circumference Z was −2.53 (95% CI −2.96 to −2.11; p<0.0001), 21/29 with Z below −2; in probands, −2.55 (CI −3.12 to −1.98); in a comparison group of 50 patients referred for aCGH in the same period, −0.62 [8]. The proportion with microcephaly varies between series (22% in Simons VIP, 43% in GeneReviews, 51% in Edwards, 60% in the Turkish cohort) and is higher in females [1, 12, 14, 56]. Short stature and poor weight gain are frequent, about 19% have dysphagia, and no endocrine cause, namely growth hormone deficiency, has been identified [1, 12].

Development and cognition. Most have delay, generally mild, sometimes selective (mainly gross motor) and sometimes global; about 25% have mild ID or lifelong learning difficulties [1]. In the Linden family cohort, children with the deletion had lower full-scale (p=0.002), performance (p<0.001) and verbal (p=0.029) intelligence quotient (IQ) than family controls and spatial cognition deficits (planning z −1.46; spatial working memory z −2.23); adult carriers also had lower IQ [55]. The deletion and duplication share borderline cognitive functioning, fine and gross motor deficit, speech articulation disorders and hypotonia [3, 14].

Eyes. About one third have ocular anomalies: strabismus, nystagmus, nasolacrimal duct obstruction, chorioretinal and iris colobomas, microphthalmia, hypermetropia, Duane anomaly and congenital or pulverulent nuclear cataracts [1, 12]. Cataracts affect 33% of carriers in Simons VIP [14]. In the Mefford series, a patient with a de novo deletion had subtle pulverulent nuclear cataracts and patent ductus arteriosus diagnosed only at 4 years after targeted studies prompted by the deletion, and a patient with normal cognition had bilateral anterior sutural congenital cataracts, with a sister carrying the same deletion affected by dense congenital cataracts [18].

Neurological. Neurological examination is generally normal; hypotonia and tremor are frequent (tremor in 44% in Bernier and Edwards) [1, 12, 14]. Seizures, tonic-clonic or absences, occur in ~23% according to GeneReviews, 29.8% in Edwards and 19% (7/36 children, unprovoked seizures) in Linden, many with onset in the first year [1, 12, 55]. Agenesis of the corpus callosum, neuronal migration anomalies and hydrocephalus have been described [1].

Cardiovascular. Patent ductus arteriosus, truncus arteriosus, ventricular and atrial septal defects, tetralogy of Fallot, bicuspid aortic valve, ascending aortic dilatation (without progression data), aortic regurgitation, coarctation, interrupted aortic arch, supravalvular aortic stenosis, anomalous origin of the right coronary artery, pulmonary valve stenosis and transposition of the great arteries have been described; in rhythm, sinus bradycardia and long QT [1, 63]. Heart disease is more frequent in females [1, 56]. Case-control data are in 3.4.

Genitourinary and gastrointestinal. Vesicoureteral reflux, hydronephrosis, renal asymmetry, unilateral renal agenesis, inguinal hernia and cryptorchidism; Mayer-Rokitansky-Küster-Hauser syndrome in two female carriers [1, 64]. Chronic constipation, dysphagia, gastro-oesophageal reflux and slow gastric emptying, sometimes requiring gastrostomy [1, 12].

Skeletal, hearing and infections. Craniosynostosis (one metopic), mild to severe scoliosis, joint hyperlaxity, brachydactyly, broad thumbs and halluces, duplicated or bifid hallux, 5th finger clinodactyly, clubfoot, flat foot, syndactyly or overlapping toes and polydactyly [1, 3]. Sensorineural hearing loss in at least 5 individuals and hearing loss of unspecified type in another 6; recurrent infections, including otitis media, in a minority [1, 15]. Busè and colleagues described congenital hypothyroidism in a series of seven patients [65].

Behaviour and psychiatry. ASD, ADHD, anxiety, mood disorders, sleep disorders and self-injurious behaviours [1]. In the Linden cohort (68 carriers; 51 children and 17 adults, compared with family controls), 30/49 children (61%) had a psychiatric diagnosis versus 3/28 (10.7%) of controls, 28/50 (56%) a neurodevelopmental disorder versus no controls, 12/49 (24%) anxiety and 9/49 (18%) conduct disorder; in adults, psychiatric disorder in 59% versus 28% (OR 4.0; p=0.03) and mood disorder in 35% versus 9% (OR 6.0) [55]. Schizophrenia is covered in 3.3.

3.2. Distal duplication: phenotype in clinical series

The duplication has fewer and more heterogeneous data than the deletion, with no entry of its own in GeneReviews, which records at least 47 individuals published up to 2023 [1]. The largest review, by Dolcetti and colleagues, gathered 107 individuals (59 children and 48 adults) from 76 families, 70 of them from the literature, and included 7 adults from Toronto identified in studies of schizophrenia and tetralogy of Fallot; of the 60 probands with known breakpoints, 56 (93.3%) were class I and 4 (6.7%) class II, analysed together [13]. Table 6 compares the series.

Table 6. Series of distal duplication carriers.

Head circumference and growth. In the 24 duplication carriers of Brunetti-Pierri, the mean head circumference Z was +0.95 (95% CI 0.06 to 1.83; p<0.05), with greater dispersion than in the deletion and 10/24 with Z above +2; in probands, +1.15 (CI 0.03 to 2.28); the difference between deletion and duplication had p<0.0001 [8]. The OMIM synopsis records macrocephaly in half of cases, with normal stature [5]. In the adults of Dolcetti, macrocephaly and criteria for possible overgrowth syndrome were frequent, together with anomalies of possible connective tissue origin, such as carpal tunnel syndrome [13].

Face, neurological and other systems. Prominent forehead or frontal bossing and hypertelorism are the most cited features and visible in the Brunetti-Pierri photographs [4, 8]. Hypotonia, tremor, hypoplasia of the corpus callosum and cerebellar vermis, rare seizures and hydrocephalus have been described [1, 4, 5]. Gourari and colleagues reviewed 13 patients with epilepsy and 1q21.1 duplication, 10 of them with a proximal duplication and only 3 with a pure distal duplication, with no segment common to all [66]. Orphanet also lists cryptorchidism, hypospadias, strabismus, glaucoma, cataract, hip dysplasia or dislocation, clubfoot, gastro-oesophageal reflux and arthrogryposis, with frequencies derived from proband series [4]. In Buchan's series of adolescent idiopathic scoliosis (143 patients), the 1q21.1 duplication appeared in 3 (2.1%) versus 1/1079 controls (0.09%) [67]. Busè described trigonocephaly in a duplication carrier [65]. Anorectal malformations have been described in three patients, including the case in section 10 [11].

Development and cognition. In the Linden cohort, children with the duplication had lower full-scale, performance and verbal IQ than family controls and reduced spatial working memory (z −2.71), but adults did not differ from controls in IQ [55].

3.3. Neuropsychiatry: case-control and population associations

Estimates of psychiatric risk depend on study design and are only comparable when the population and denominator are known (Table 7). In schizophrenia, the distal deletion is one of the most reproducible risk CNVs: GeneReviews records it in 0.2–0.6% of people with schizophrenia [1, 35–37]. Rees and colleagues (Cardiff) studied a British sample of 6882 cases and 6316 controls and meta-analysed it with previous studies: the deletion was in 33/19,056 cases (0.17%) and 17/81,821 controls (0.021%), OR 8.35 (95% CI 4.65–14.99; p=4.1×10⁻¹³), and the duplication in 21/16,247 cases (0.13%) and 24/64,046 controls (0.037%), OR 3.45 (CI 1.92–6.20; p=9.9×10⁻⁵); the authors noted that the evidence for the duplication, previously supported by a single study, was strengthened [68]. The Psychiatric Genomics Consortium (PGC), with 21,094 cases and 20,227 controls of European ancestry analysed in a centralised pipeline, found for the combined test of 1q21.1 losses and gains 60 cases versus 14 controls (OR 3.8; CI 2.1–6.9; p=1.5×10⁻⁶), with genome-wide significance for losses; ORs separated by deletion and duplication are only in the supplements [69]. In ADHD, the deCODE study (8883 affected individuals from Iceland and Norway versus 155,122 Icelandic controls and Norwegian controls) gave for the distal duplication frequencies of 0.146% versus 0.0454% (OR 3.44; CI 1.67–6.52; adjusted p 0.0020) and for the distal deletion 0.0788% versus 0.0288% (OR 2.68; CI 0.92–6.44; p 0.054, not significant) [25].

In ASD, the Simons Simplex Collection (2591 families) identified five de novo CNVs at 1q21.1, all duplications, in probands (q 0.00002), and nine (one deletion and eight duplications) with the Autism Genome Project data; these are associations of de novo CNVs against unaffected siblings, not case-control ORs [70]. Mefford found the duplication in 2 of 141 patients with autism (p=0.002 versus controls) [18]. In the sources consulted there is no 1q21.1-specific case-control OR for ASD. Danish population data from iPSYCH 2012 (case-cohort of 86,189 born between 1981 and 2005, followed until 2012) associate 1q21.1 CNVs with ASD and ADHD and, for the deletion, with major depression (HR 5.8; CI 1.5–22.2) and bipolar disorder only in men (HR 17; CI 1.5–189.3); schizophrenia risks were generally lower than in case-control studies and trajectories were similar for deletion and duplication; only the abstract was read [71].

Table 7. Psychiatric association studies.

Sources: [3, 25, 55, 68–73].

Itsara and colleagues, comparing 2500 individuals from the general population with nine genomic studies, associated the deletion with autism and schizophrenia and the duplication with autism, ID and schizophrenia [74]. In the Sahoo series (38,779 individuals referred for microarray), carriers of schizophrenia susceptibility loci, including 1q21.1, presented in childhood with speech and developmental delays and behavioural problems [19].

3.4. Congenital heart disease: phenotypic specificity

Case-control studies show that the distal deletion and duplication confer different cardiac risks (Table 8). In the British and European study by Soemedi (948 patients with isolated tetralogy of Fallot, 1488 with other isolated congenital heart defects and 10,910 controls), the duplication was in 8/948 patients with tetralogy versus 3/10,910 controls (OR 30.9; 95% CI 8.9–107.6; population attributable risk 0.92%) and in none of the other cardiac patients, whereas the deletion was in 3/1488 patients with other heart defects versus 4/10,910 controls (OR 5.5; CI 1.4–23.2) and in none with tetralogy. Small duplications, of 100–200 kb, that had only GJA5 in common were in 3/948 patients with tetralogy versus 2/6760 controls (OR 10.7; CI 1.8–64.3), which led the authors to propose GJA5 as the critical gene of the cardiac phenotype [24]. In the five tetralogy cases with a duplication transmitted by an unaffected parent, transmission was maternal (p=0.06, not significant) [24].

Table 8. 1q21.1 CNVs in congenital heart disease cohorts.

Digilio's review concludes that 1q21.1 heart defects are anatomically heterogeneous [63]. In mice heterozygous for Cx40 there are structural cardiac anomalies in 18% [34]. The ascending aortic dilatation described in the deletion has no progression data [1].

3.5. Unascertained adult carriers: population data

In the UK Biobank (420,247 middle-aged adults of white British or Irish ancestry), Kendall and colleagues assessed 7 cognitive tests and 4 measures of functioning (educational attainment, occupation, income and Townsend deprivation index). The 112 distal deletion carriers had significantly worse results in 7 of the 11 measures, with a mean effect of −0.27 on the tests; the 176 distal duplication carriers in 5, with a mean effect of −0.08; the 436 proximal duplication carriers in 5, with a mean effect of −0.12; the 75 proximal deletion carriers in none (Table 9). ClinGen summarises these data as 5 of 7 cognitive measures in the distal deletion, 0 of 7 in the distal duplication and proximal deletion and 1 of 7 in the proximal duplication [6, 9, 21]. The authors found a correlation between penetrance and mean cognitive effect (r 0.74) and between penetrance and the mean number of children of carriers (r 0.78); limitations include brief tests and the healthy participation bias of the UK Biobank [21]. In Iceland, control carriers of schizophrenia or autism risk CNVs have cognitive performance intermediate between patients with schizophrenia and population controls [77]; Kendall's earlier study of 152,000 UK Biobank participants had already shown worse cognitive performance in carriers of pathogenic CNVs [78].

Table 9. 1q21.1 CNVs in the UK Biobank (Kendall 2019).

Source: [21].

Crawford and colleagues tested 54 CNVs against 58 common medical phenotypes in the UK Biobank (381,452 non-carriers). Diabetes, hypertension, obesity and renal failure were the outcomes affected by the largest number of CNVs; for the 1q21.1 duplication, the OR for diabetes increased after adjustment for body mass index (BMI), which suggests a direct effect on diabetes not mediated by obesity [38]. The ORs per CNV are in the supplements, which were not read. Only 34 of the 14,791 CNV carriers had schizophrenia, 17 developmental delay and 4 autism, reflecting the healthy volunteer bias [38]. In ENIGMA-CNV, cognitive deficits were intermediate in duplication carriers and greater in deletion carriers, possibly mediated by intracranial volume and cortical area [33].

3.6. Proximal region: duplication and deletion without TAR

Proximal duplication. Phenotypes are variable, mostly non-specific and sometimes inconsistent (developmental delay or ID, hypotonia, poor weight gain or feeding difficulties, seizures, behavioural problems), and the duplication is generally inherited, typically from an unaffected parent [6]. In the Rosenfeld series (20 new cases), 12/16 had developmental delay or ID, 9/16 dysmorphism, 5/7 brain anomalies, 5/10 poor weight gain and 6/14 behavioural problems; the 7 probands with studied inheritance and the 12 of the second cohort had inherited the duplication [6, 7]. Levy and colleagues, in an Israeli database of 27,990 clinical microarrays and another of 80,000 tests with and without clinical indication, identified 62 carriers (28 index cases and 34 relatives) and a frequency of ~1:1000 in both cohorts. Of the 13 index cases ascertained for congenital anomalies, autism, seizures or delay, 11 were postnatal (delay 6, ASD 4, congenital anomalies or dysmorphism 4); in a comparison group of 15 carriers diagnosed prenatally at the parents' request, with normal nuchal translucency and anomaly scan, the 4 with 3–7 years of follow-up had normal development; no duplication was de novo [16]. In the French series of Bourgois (9 new cases), 7/9 had delay or adapted schooling and 7/9 psychiatric or behavioural conditions, but 3 of the transmitting parents also had delay or learning difficulties [6, 15]. Pang described 7 carriers with inconsistent features [62]; Buchan, inconsistent segregation in 3 families with adolescent idiopathic scoliosis [6, 67]; Busè, psychomotor delay, dysmorphism and broad fingers and thumbs in a carrier with a normal mother [6, 65]. In epilepsy, 10 of the 13 patients reviewed by Gourari had a proximal duplication [66]. The TS 1 score and the ID penetrance of 1.0% summarise this evidence [6, 10].

Proximal deletion without TAR. Rosenfeld compared 13 probands with a proximal deletion without TAR with 35 with TAR: delay or ID 11/12 versus 1/28, dysmorphism 8/12 versus 2/26 and behavioural problems 7/13 versus none; the authors acknowledge ascertainment bias. Of the deletions with studied inheritance, 6/17 (35%) were de novo [6, 7]. Later reports (Bourgois, Pang, Leitão and colleagues and Wen and colleagues, the latter with two fetuses without developmental phenotype or TAR on postnatal follow-up, both inherited from asymptomatic mothers) maintain the non-specific picture, and in the UK Biobank the proximal deletion had no cognitive effect [6, 21]. For this reason, ClinGen does not assign it haploinsufficiency for a dominant phenotype [6].

3.7. Class II CNVs

In the Brunetti-Pierri series, 6 of the 21 probands with a deletion had deletions extended into the TAR region, of ~2 Mb, and one of the 17 duplications was class II [3, 8]. Rosenfeld described 13 combined proximal and distal microdeletions, two of them with "partial" TAR [7]. The phenotype is similar to that of the distal deletion (dysmorphism, delay, cardiac and genitourinary anomalies), with isolated reports of clavicular pseudarthrosis, anomalous coronary artery and an extra 5th finger crease [1, 41]. In the Edwards series, four patients with proximal and distal deletions were analysed separately from the 43 with a distal deletion [12].

3.8. Prenatal phenotype

The fetal phenotype is non-specific. In a Chinese series of 16 deletions and 13 duplications diagnosed by SNP array, 8/16 deletions had ultrasound anomalies (3 urinary, 4 growth restrictions, 3 lateral ventriculomegalies, 1 aortic stenosis) and 6/13 duplications (4 cardiovascular, 1 growth restriction, 1 enlarged posterior fossa, 1 ventriculomegaly) [79]. In another Chinese series of 20 consecutive cases (2017–2024), ultrasound anomalies appeared in 8/12 deletions (growth restriction, heart disease) and 3/8 duplications (nasal bone hypoplasia), with no specific marker [80]. In a third, of 43 fetuses, 11/20 deletions mainly had renal and musculoskeletal anomalies and increased nuchal translucency, and 11/23 duplications nasal bone, cardiovascular and neurological anomalies and increased nuchal translucency [81]. A mosaic deletion has been described in a fetus with megacystis and bilateral arthrogryposis of the hands [82]. These series are from single centres, with short postnatal follow-up, and the decision to terminate the pregnancy removes the most informative cases from follow-up.

4. Clinical Recognition and Red Flags

4.1. When to suspect

There is no clinical picture that allows a 1q21.1 CNV to be suspected at the bedside; the diagnosis almost always arises from a CMA requested for developmental delay, ID, ASD or multiple congenital anomalies, or as a finding of a prenatal microarray [1, 32]. The findings that GeneReviews considers suggestive of the deletion are hypotonia, developmental delays, ID typically mild to moderate, microcephaly, poor weight gain, neurobehavioural manifestations (behavioural crises, ADHD, aggression, sleep disorders, ASD), seizures, ophthalmological involvement (strabismus, nystagmus), hearing loss, joint hyperlaxity, mild non-specific dysmorphism and a family history compatible with dominant inheritance; the absence of a family history does not exclude the diagnosis, because there are carriers without findings [1]. By age and context, Table 10 brings together the situations in which a 1q21.1 CNV enters diagnostic reasoning.

Table 10. Clinical contexts of suspicion.

4.2. Red flags and urgent signs

Carriers may have problems that require prompt action and that depend not on the CNV itself but on the manifestation. Severe congenital heart disease is the main cause of death described: in the Turkish cohort, two children with a distal deletion died from severe cardiac complications during follow-up [56]. Seizures often begin in the first year of life [1]. Dysphagia, choking, frequent respiratory infections and food refusal suggest oromotor dysfunction and risk of aspiration and should prompt a swallowing study [1]. Visually significant congenital cataract is a functional emergency, because surgery is usually performed at around 6 weeks if unilateral and at 6–8 weeks if bilateral [83]. Long QT, described in a deletion carrier with a second variant in KCNH2, and ascending aortic dilatation justify the initial electrocardiogram and echocardiogram [1]. Thrombocytopenia or a radial anomaly in a carrier of a CNV that includes the proximal region requires TAR to be excluded [6]. There is no newborn screening for these CNVs.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criterion

The diagnosis is molecular: detection of a heterozygous deletion or duplication of the recurrent interval. For the distal deletion, GeneReviews defines it as the ~0.8 Mb deletion at GRCh38 chr1:147,105,904–147,917,509, the ClinGen minimal coordinates, which vary slightly with array design; the calculated size differs from the expected one because of the segmental duplications at the breakpoints, and the designations of 0.8, 1.2 and 1.35 Mb correspond to the same entity [1, 9]. The same applies, by reciprocity, to the duplication. The proximal CNVs are defined by the ClinGen BP2–BP3 coordinates [6].

5.2. Tests in order and their limits

Table 11. Detection methods.

CMA does not detect balanced rearrangements or low-level mosaicism, which account for less than 1% of causes in the 2010 consensus [26]. A CMA negative for 1q21.1 does not exclude other causes of the phenotype, and a positive CMA does not exclude them either: a dual diagnosis is possible and should be sought when the phenotype is severe or atypical, especially if the CNV was inherited from an unaffected parent [1, 57].

5.3. Classification and report content

The technical standards of the American College of Medical Genetics and Genomics (ACMG) and ClinGen for constitutional CNVs (2020) use a quantitative scoring system with five classes. CNVs associated with consistent phenotypes in multiple publications, "with well-documented penetrance and expressivity, even if reduced and/or variable", and those that completely overlap an established dosage-sensitive region are classified as pathogenic. The standards recommend decoupling the classification of the CNV from the implications for the individual, not classifying the same CNV differently according to the reason for referral and separating primary from secondary or incidental findings in the report [86]. With current ClinGen scores, the distal deletion (HI 3) and distal duplication (TS 2) meet the criteria for pathogenicity with reduced penetrance; the proximal duplication (TS 1) and the isolated proximal deletion (HI 0, recessive disease) do not have this status for a dominant phenotype, and their final classification depends on the case score [6, 9, 86]. The report should state the genome assembly, the minimal and maximal coordinates, the size, the copy number, the breakpoints (BP), the class (I or II, distal or proximal), the OMIM genes included, the classification, explicit mention of incomplete penetrance and variable expressivity, the recommendation to study the parents and, when the proximal region is included, reference to the risk of TAR in the presence of a hypomorphic RBM8A allele [1, 6, 86].

5.4. Diagnostic algorithm

The International Standard Cytogenomic Array (ISCA) consensus, based on 33 studies with 21,698 patients, showed a CMA yield of 15–20% in unexplained developmental delay, ID, ASD or multiple congenital anomalies, compared with ~3% for karyotype, and recommended CMA as first line, reserving karyotype for evident chromosomal syndromes, a family history of rearrangement or multiple miscarriages [26]. The 2021 ACMG guideline recommends considering exome or genome as a first- or second-tier test in patients with congenital anomalies with onset before 1 year or with developmental delay or ID with onset before 18 years [84]. The Oxford Desk Reference algorithm, adapted from Miller, follows these steps after a CMA with an abnormal result or one of uncertain significance: consultation of the DECIPHER database for gene content, phenotypes and typical inheritance; parental studies, with confirmation in the proband by FISH, G-banding, qPCR or MLPA when necessary; interpretation according to inheritance (de novo, inherited from an affected parent, inherited from an unaffected parent, parent carrying a balanced rearrangement) and caution regarding incomplete penetrance, unmasking of a recessive allele, imprinting, amplification of a parental duplication and complex inheritance [32]. In 1q21.1 CNVs, inheritance from an unaffected parent does not make the CNV benign; it means incomplete penetrance and requires a search for other contributors when the phenotype is disproportionate [32, 86].

5.5. Parental studies, mosaicism and prenatal diagnosis

Parental testing is recommended. If the CNV is present in neither parent, it is de novo or results from germline mosaicism or combined somatic and germline mosaicism; study of parental leucocytes does not detect exclusively germline mosaicism and may miss low-level somatic mosaicism [1]. Low-level mosaicism may escape CMA, and a mosaic 1q21.1 deletion has been described in a fetus [26, 82]. Prenatal diagnosis and preimplantation genetic testing (PGT) are described in section 8.

6. Differential Diagnosis

The differential is broad because the phenotype is non-specific and all manifestations can occur in other genomic disorders [1]. In practice, the differential is made on two levels: before testing, between the causes of each manifestation (delay, micro- or macrocephaly, cataract, heart disease), and after testing, between the 1q21.1 CNV as a sufficient explanation and the CNV as one of several contributors (Table 12).

Table 12. Differential diagnosis.

The penetrances of the comparator CNVs are those of Rosenfeld (2013), which measure the risk of any phenotype prompting microarray and are not comparable with Goh's ID penetrances [10, 23]. The distal deletion is distinguished from class II by the proximal breakpoint: class II includes RBM8A and requires TAR to be considered if there is a radial anomaly or thrombocytopenia [6, 7]. In 13 patients with epilepsy and a duplication reviewed by Gourari, most had a proximal duplication, and the causal relationship with epilepsy has not been established [66]. Cataract in a distal deletion carrier may result from the CNV or from another cause, and the assessment should be that of any paediatric cataract [1, 83]. The presence of a pathogenic variant in another gene, as in the patient with long QT and a KCNH2 variant, should be sought when there are manifestations poorly explained by the CNV [1].

7. Treatment and Risk Management Strategies

7.1. Principles

There are no published clinical practice guidelines for 1q21.1 CNVs, nor any cure or treatment directed at the mechanism; management is supportive, guided by the manifestations and by surveillance of known risks [1]. The GeneReviews recommendations were written for the distal deletion, but the overlap of risks (heart disease, delay, psychiatric disorders, ocular anomalies) justifies applying them to the distal duplication with the adaptations in Table 13; for the proximal duplication, whose ID penetrance is 1.0%, assessment should be directed at the phenotype that prompted testing and at the search for another cause [1, 6, 10]. The recommendation of routine cardiac assessment in all carriers comes from the authors of the Turkish cohort, who recorded two cardiac deaths in children with the deletion [56].

7.2. Evaluation after diagnosis

Table 13. Recommended initial evaluations (adapted from GeneReviews for the distal deletion).

7.3. Treatment of manifestations

Table 14. Treatment by manifestation.

7.4. Development, communication and behaviour

Physiotherapy for gross motor skills reduces the risk of contractures and scoliosis, and occupational therapy works on fine motor skills. Oromotor dysfunction should be assessed at each visit, with a swallowing study in the presence of choking, poor weight gain, frequent respiratory infections or food refusal; thickening or chilling foods and using a nasogastric tube or gastrostomy are the options in severe cases. Augmentative and alternative communication, introduced by a speech and language therapist, does not impair speech development [1]. ASD interventions include applied behaviour analysis by a certified professional, and developmental paediatrics guides behavioural strategies and medication, for example for ADHD, when needed [1]. The organisation described in GeneReviews (early intervention from 0 to 3 years, developmental preschool with an individualised education plan from 3 to 5, transition plan in adolescence) follows the US system and varies between countries [1].

7.5. Drugs

No drug is indicated for 1q21.1 CNVs, and there are no doses studied specifically in carriers; the response of these patients has not been evaluated in trials. Drugs used for epilepsy, ADHD, irritability associated with ASD, anxiety, depression or psychosis follow the general indications, doses and precautions of each. Table 15 gives, for the drugs cited in the sources of this article, the doses from the Food and Drug Administration (FDA) labels for the authorised indication closest to the manifestation to be treated and the differences in the European and Portuguese summary of product characteristics (SmPC); this is an extrapolation from analogous conditions, not doses validated in these CNVs. The two differences with the greatest practical consequence are the absence, in the EU, of an indication for aripiprazole in irritability associated with autism, which makes this use off-label in Portugal, and the European restriction of methylphenidate to patients aged 6 to 17 years in the Rubifen® SmPC. The sources consulted do not include the package inserts of the Brazilian Health Regulatory Agency (ANVISA) [88–95].

Table 15. Reference posology of the drugs cited (FDA labels and European and Portuguese SmPCs; extrapolation from analogous indications).

The prior cardiac assessment required by the methylphenidate label is of particular relevance in these CNVs, which are associated with congenital heart disease and long QT; the echocardiogram and electrocardiogram of the initial evaluation (Table 13) serve this purpose [1, 91]. Two isolated reports describe off-label management: aripiprazole reversed gastroparesis in a child with a 1q21.1-q21.2 microdeletion [87], and a 10-year-old girl with a distal duplication, ASD and focal epilepsy remained seizure-free for about one year after switching from high doses of oxcarbazepine to lamotrigine and eliminating caffeine, whose intake in large quantities preceded seizure clusters [66]. Neither article publishes the doses used, and neither is a basis for recommendation. The increased response to psychostimulants in the mouse model of the deletion [49] has no studied clinical correlate.

7.6. Regulatory status

Table 16. Comparative regulatory situation.

Source: search of ClinicalTrials.gov and recent literature [98]. A negative search does not demonstrate the absence of unpublished processes.

7.7. Registered trials and studies

Table 17. Registered clinical studies.

There are no interventional trials, positive or negative, to compare. The only controlled data on carriers come from observational studies, and the effects described in cellular models (modulation of calcium channels, BPTF, CHD1L) are at the preclinical stage [44, 48, 51].

7.8. Developments in the last 12 months

Table 18. Publications and updates between October 2025 and October 2026.

The search did not identify authorisations, opinions or regulatory communications about these CNVs in the period.

7.9. Cardiac and ocular manifestations: applicable guidelines

General guidelines apply to organ manifestations. In atrial fibrillation, the 2023 American guideline of the American College of Cardiology, American Heart Association, American College of Clinical Pharmacy and Heart Rhythm Society (ACC/AHA/ACCP/HRS) considers that, in patients with onset before 45 years without obvious risk factors, referral for genetic counselling, testing for rare variants and surveillance for cardiomyopathy or arrhythmia syndromes "may be reasonable" (class 2b, level B-NR); the 2022 consensus of the European, North American, Asia-Pacific and Latin American heart rhythm societies (EHRA/HRS/APHRS/LAHRS) recommends analysing SCN5A, KCNQ1, MYL4 and truncating TTN variants in familial atrial fibrillation with onset before 60 years and classifies GJA5 as a rare gene, outside the recommended set; the 2024 European Society of Cardiology (ESC) guideline is the European reference for general management of the arrhythmia [42, 100–102]. There are no data on atrial fibrillation in carriers of 1q21.1 CNVs in the sources consulted. In congenital cataract, management follows the expert review by Bell and colleagues: early surgery, red reflex screening in the newborn and lifelong glaucoma surveillance after lensectomy [83].

7.10. Pregnancy, perioperative care and transition to adulthood

The sources consulted do not describe specific pregnancy complications in carriers or specific perioperative recommendations; preoperative assessment should include known heart disease, the electrocardiogram (long QT described) and dysphagia [1]. Transition to adulthood is the period of greatest psychiatric risk: in the Linden cohort, adults with a distal deletion or duplication had more frequent psychiatric and mood disorders than family controls (OR 4.0–10.0) [55], the distal deletion increases the risk of schizophrenia ~8-fold [68], and in the UK Biobank the duplication is associated with diabetes independently of BMI [38]. GeneReviews recommends offering genetic counselling to young adult carriers or those at risk before reproductive age [1].

7.11. Guideline recommendations and divergences

Table 19. Applicable guidelines and consensus statements.

8. Reproductive Options and Family Counselling

8.1. Mode of transmission

Distal 1q21.1 CNVs are transmitted in an autosomal dominant manner, by either parent, and severity does not appear to vary with the parent of origin [1]. Dominant transmission does not mean dominant expression: penetrance is incomplete and expressivity variable, so that the carrier parent may have a phenotype similar to that of the child, usually milder, or have no manifestations at all [1]. In the distal deletion, published series give proportions of de novo deletions between 18% and 35% of probands: 7 of 14 probands with parental studies had the deletion in a parent in the Mefford series, 9 of 11 deletions were inherited in that of Brunetti-Pierri and 8 of 23 were de novo in that of Edwards [1, 8, 12, 18]. In the distal duplication, inheritance is the rule: 12/12 duplications inherited in the Bourgois series (10 maternal and 2 paternal), 13/14 in Simons VIP and 5/21 de novo in the Bourgois literature review [9, 14, 15]. The proximal duplication was inherited in all informative cases of Rosenfeld (7/7 and 12/12 in the second cohort) and Levy (10/10), and none was de novo [6, 7, 16].

The proportion of transmitting parents with manifestations is the most useful information for explaining penetrance to a family. In the distal deletion, about 25% of the transmissions described in GeneReviews came from a parent with a normal phenotype, and in the Edwards series 9 carrier parents had variable findings (behaviour, microcephaly, speech delay, heart disease, cerebral palsy, ocular anomalies) and 4 were unaffected [1, 12]. In the Bourgois review, only 1 of 20 published deletion-carrier parents had developmental delay or learning difficulties; in the duplication, the proportion was 2/16 in published cases and 4/12 in new cases, and ClinGen summarises that in the duplication the proportion of affected parents approaches 25% [9, 15]. These proportions describe families ascertained through an affected child, not the probability of manifestations in a carrier identified at random.

8.2. Effect of sex and parental origin

Two observations from small cohorts suggest an effect of maternal origin, without replication in the sources read. In tetralogy of Fallot with a duplication transmitted by an unaffected parent, transmission was maternal in 5 of 5 cases (p=0.06) [24]. In the proximal duplication, the nine clinical cases with tested origin were maternally inherited, and the authors proposed a greater impact in boys who inherit it from the mother [16]. GeneReviews does not identify a difference in severity by parental origin in the distal deletion, and neither does the Turkish cohort of Mutlucan Köseoğlu [1, 56]. None of these observations supports, so far, a different risk according to the sex of the transmitting parent.

8.3. Recurrence risks

Table 20. Recurrence risks by scenario.

An absence of family history can only be interpreted after testing both parents: an apparently history-free family may have an asymptomatic carrier parent [1]. When the phenotypes of parent and child diverge greatly, the Oxford Desk Reference suggests considering, in addition to incomplete penetrance and the complex inheritance typical of susceptibility loci, unmasking of a recessive phenotype by a variant on the other allele of a gene in the region, extension of the deletion or amplification of a duplication on transmission [32]. For the proximal region, unmasking of a recessive phenotype is the mechanism of TAR syndrome [40].

8.4. Cascade testing and testing of minors

Genomic study of the proband's parents is recommended [1]. GeneReviews recommends testing the proband's siblings with a method that detects the deletion, to identify early those who would benefit from developmental surveillance; in a relative of a proband with a known deletion, targeted methods can be used (fluorescence in situ hybridisation, FISH; quantitative PCR, qPCR; multiplex ligation-dependent probe amplification, MLPA), which do not measure the extent of the CNV [1]. The Oxford Desk Reference notes that there is no consensus on cascade testing in CNVs with incomplete penetrance, because of prognostic uncertainty [32]. The two positions are reconciled by the reason for testing: in a minor sibling, the result has direct clinical utility (developmental surveillance, echocardiogram, ophthalmological assessment), whereas in an asymptomatic adult it serves mainly reproductive planning and should be decided by the person, after counselling. GeneReviews recommends offering genetic counselling to young adult carriers or those at risk, before reproductive age [1]. The information should distinguish penetrance for ID, penetrance for any phenotype prompting a microarray and the frequency of psychiatric diagnoses in children from ascertained cohorts, which are not interchangeable (section 2.6).

8.5. Prenatal diagnosis

Prenatal testing by chorionic villus sampling or amniocentesis is possible once the CNV has been identified in the family; a prenatal microarray requested for another indication may also detect it in a pregnancy without known risk; in either case, the prenatal finding does not predict the phenotype [1]. The Oxford Desk Reference describes prenatal diagnosis as useful for reassurance after a de novo CNV and as an option for families in which the CNV has caused disease, calls for caution in CNVs with variable penetrance and recommends a long consultation, with appropriate consent, when the carrier parent has learning difficulties; when the CNV has no apparent phenotype in the family, prenatal diagnosis may not be indicated [32]. There is a divergence of perspective on prenatal testing for conditions of variable expression, and most centres consider it a personal decision [1].

The Chinese prenatal series show the weight of these decisions. In the Liu series (20 consecutive cases from 2017 to 2024), 10 pregnancies were terminated, 80% of them for de novo CNVs, and the 9 live births had no evident anomalies at follow-up of 3 months to 5 years [80]. In the Luo series, there were 9 terminations among 16 deletions and 4 among 13 duplications; at follow-up, one live-born child with a deletion had epilepsy and another language and motor delay, and one with a duplication had hearing impairment and another speech delay [79]. The authors recommend integrated counselling and postnatal neurodevelopmental surveillance [79, 80]. In the proximal duplication, the 4 carriers identified by prenatal microarray requested by the parents, with normal nuchal translucency and anomaly scan and 3–7 years of follow-up, had normal development [16]. The associated ultrasound phenotype is in section 3.8.

8.6. Prenatal reporting of low-penetrance CNVs

The Oxford Desk Reference notes that some laboratories analysing prenatal microarrays for increased nuchal translucency or fetal malformation do not routinely report CNVs with substantially incomplete penetrance [32]. Goh and colleagues propose considering not reporting 14 CNVs with ID penetrance close to 0%, among them the proximal 1q21.1 duplication, especially prenatally, arguing that non-reporting reduces anxiety and unnecessary investigation; for subtle cognitive variation they suggest framing ability within the spectrum of human normality [10]. This is an authors' proposal and not a guideline; the sources consulted do not include a prenatal reporting guideline specific to these CNVs. The distal deletions and duplications do not belong to this group and continue to be classified as pathogenic with reduced penetrance according to the ACMG/ClinGen standards [9, 10, 86].

8.7. Preimplantation genetic testing

PGT is possible once the CNV has been identified in the family [1]. In a Chinese couple in which the father had a recurrent 1q21.1 duplication, optical genome mapping confirmed the tandem orientation and location of the duplication, and PGT by linkage analysis, concordant with high-resolution aneuploidy screening (PGT-A), allowed transfer of an embryo without the paternal duplication [85]. The decision to use PGT for a CNV with an ID penetrance of 4–10% is personal and should be based on the figures in Table 3.

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

Epidemiological data on 1q21.1 CNVs belong to three types that cannot be mixed: the frequency in patients referred for microarray (clinical cohorts enriched for developmental delay, ID, ASD and congenital anomalies), the frequency measured in adults from the general population not selected by phenotype (UK Biobank, gnomAD) and the birth prevalence modelled from clinical data. GeneReviews summarises the distal deletion as present in about 0.2% (46/22,563) of individuals with delay, ID or congenital anomalies studied by microarray and in about 0.01% (1/6882) of the general population, the latter an indirect estimate [1, 22]. For the duplication, Orphanet records "46 cases or families" and a prevalence class of "<1/1,000,000"; the value is a count of published cases and is incompatible with microarray and population frequencies, so it should not be read as a prevalence [4]. For the deletion, Orphanet gives an unknown prevalence [2].

Table 21. Frequency of 1q21.1 CNVs by type of study and population.

Frequencies in clinical cohorts range from 0.16% to 0.48% for the distal deletion and from 0.10% to 0.49% for the distal duplication, according to the indication, platform and inclusion criteria of each laboratory [8, 18–20, 23, 105]. The population frequency measured in the UK Biobank (0.027% and 0.042%) is several times higher than the prevalence modelled by Gillentine (1/6882 ≈ 0.015% and 1/6309 ≈ 0.016%), because the model assumes high penetrance and is calibrated with genomic disorders of almost complete expression [21, 22]. The UK Biobank, in turn, underestimates the frequency of the most affected carriers, owing to healthy volunteer participation bias: only 34 of the 14,791 CNV carriers had schizophrenia [38]. Frequencies in schizophrenia and ADHD are in Table 7.

9.2. Data by region and population

The available data come mainly from the USA and Northern Europe. The large clinical microarray cohorts come from diagnostic laboratories and consortia, among them Baylor, in Texas, and the ISCA consortium [8, 22, 105], and Simons VIP and Simons Searchlight are carrier registries with standardised phenotypic assessment [14, 29]. In Europe, the UK Biobank gives frequencies in white British and Irish adults [21]; deCODE studied the Icelandic population, with Norwegian replication, for ADHD (155,122 Icelandic controls) [25] and cognitive performance [77]; the iPSYCH 2012 cohort followed people born in Denmark between 1981 and 2005 [71]; the PGC schizophrenia consortium analysed 21,094 cases and 20,227 controls of European ancestry [69]; Soemedi's heart disease study included patients from the United Kingdom and Europe and French and British controls [24]; the Bourgois series is French [15]; and the case in section 10 is Italian [11]. Iceland and Denmark, with complete population registries, are the sources closest to population-based data; the sources consulted do not describe a founder effect, which is consistent with the recurrent formation of these CNVs by NAHR in independent families [1]. Outside Europe and the USA, there are data from Israel (frequency of ~1/1000 for the proximal duplication) [16], from Chinese prenatal series [79–81] and from a Turkish paediatric cohort of 42 children [56].

The sources consulted do not include data from Portugal or Brazil, which does not demonstrate the absence of published case series. gnomAD controls are multi-ancestry, but the affected individuals of the cohorts pooled by Goh come mainly from high-income countries, and the authors point to ancestry as a possible source of bias in the penetrance estimates [10].

9.3. Special populations

Prenatal diagnosis. 1q21.1 CNVs appear in prenatal microarrays requested for ultrasound anomalies or at the parents' request, without a specific ultrasound marker, and follow-up of live births is short (sections 3.8 and 8.5) [16, 79, 80]. Unascertained adults. Carriers identified in population studies have, on average, lower cognitive and functional performance than non-carriers, with small effects whose size depends on the CNV, greatest in the distal deletion (Table 9) [21]. Sex. Heart disease was more frequent in females in the Turkish cohort [56]; observations on maternal inheritance are in section 8.2 [16, 24]. Psychiatry. In schizophrenia cohorts, the distal deletion is present in 0.2–0.6% of patients [1].

9.4. European reference network and patient associations

In the European Union, 1q21.1 CNVs fall within the scope of ERN ITHACA (European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability), which brings together reference centres for rare congenital malformations and ID [27]. Unique (Rare Chromosome Disorder Support Group, United Kingdom) publishes guides for families on 1q21.1 microdeletions and microduplications [28, 31]; Chromosome Disorder Outreach supports families with chromosomal alterations [30]; and Simons Searchlight maintains pages on the 1q21.1 deletion and duplication and a natural history registry (NCT01238250) open to carriers [29, 98]. GeneReviews also lists MedlinePlus as an information resource, and Baylor Genetics collects clinical data on the distal deletion [1].

10. Illustrative Clinical Case

10.1. Distal duplication inherited from a healthy mother in an infant with anorectal malformation

In 2025, Minelli and colleagues, from Pescara and Chieti (Italy), described a 6-month-old boy referred for perineal fistula, a form of anorectal malformation, treated by Y-V anoplasty [11]. He was the second child of healthy, non-consanguineous parents, with no relevant family history. The pregnancy was complicated by gestational diabetes and delivery was by caesarean section at 40 weeks; at birth he weighed 4250 g (98th centile), measured 52 cm (75th centile) and had a head circumference of 38 cm (100th centile), with Apgar scores of 8 and 9. At 2 days he had respiratory distress and hypocalcaemia, treated with oral calcium gluconate. The electrocardiogram, red reflex, otoacoustic emissions, renal and spinal ultrasound and spinal radiograph were normal, and the echocardiogram showed only a patent foramen ovale. On examination there was no significant dysmorphism, but there was mild hypotonia of the upper limbs and trunk [11].

As the picture did not suggest a specific syndrome, a chromosomal microarray was requested (aCGH CytoSure ISCA v2 4×180K, mean resolution 100 kb, hg19), which showed a 1.29 Mb distal 1q21.1 duplication, chr1:146,542,653–147,828,088 (hg19), encompassing PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8 and GPR89B. Parental testing identified the same duplication in the clinically healthy mother. Figure 2 of the article shows, under the chromosome 1 ideogram, the partial duplication at q21.1 in the proband and the mother (https://pmc.ncbi.nlm.nih.gov/articles/PMC11763342/figure/cimb-47-00026-f002/); it is a microarray result figure, not a clinical photograph [11]. In ISCN notation, the result corresponds to arr[GRCh37] 1q21.1q21.2(146542653_147828088)x3 mat, built from the published coordinates (section 2.8).

It was not possible to study other relatives or to follow the course, because the family lived in another region, and the authors do not exclude the future onset of a neuropsychiatric or behavioural disorder. In their literature review they found only two other patients with anorectal malformation and a 1q21.1 duplication: a girl with a retroperineal fistula and a 1.3 Mb duplication disrupting ACP6, and a 3-year-old boy with imperforate anus and perineal fistula [11].

10.2. Clinical reading of the case

The case brings together four aspects of the class. Macrocephaly at birth (head circumference at the 100th centile) and mild hypotonia belong to the phenotype of the distal duplication, with a mean head circumference Z of +0.95 in the carriers of the Brunetti-Pierri series [8]. Transmission from a mother without manifestations illustrates incomplete penetrance: the distal duplication is inherited in most series, more often from an unaffected parent, and the ID penetrance is 4.2% [9, 10]. The association with anorectal malformation rests on three patients and is not established as part of the spectrum; the duplication may be a coincidental finding in an infant whose malformation has another cause, and the article does not mention exome sequencing [11]. Finally, the lack of follow-up makes it impossible to know whether development and behaviour will be normal, the central question of counselling.

The management in the report differs from established practice on two points. The authors propose considering genetic assessment in patients with a single congenital malformation; the ISCA consensus indicates microarray as first line in developmental delay or ID, ASD and multiple congenital anomalies, and isolated malformation is not on that list [11, 26]. And, faced with a CNV of reduced penetrance in an infant without delay, the management recommended by GeneReviews includes echocardiogram, ophthalmological and audiological assessment and surveillance of development and behaviour at each visit (sections 7.2 and 11.2), which the report could not describe [1].

10.3. Familial variability in the founding series

The facial photographs of the Brunetti-Pierri series, published with consent, show variability within families. In Figure 2 (deletion; https://pmc.ncbi.nlm.nih.gov/articles/PMC2680128/figure/F2/), probands and carrier parents share frontal bossing, deep-set eyes and a bulbous nose; in Figure 3 (duplication; https://pmc.ncbi.nlm.nih.gov/articles/PMC2680128/figure/F3/), hypertelorism and frontal bossing [8]. Subject 33 in Figure 3, aged 6 months, had a head circumference Z of +3, esotropia, hydrocephalus and advanced bone age, and the duplication came from the mother, photographed beside her son and a sibling; subject 32, aged 7 years with Z +2.6, had developmental delay and ID, scoliosis, hypospadias, Raynaud's phenomenon and ASD; subject 22, aged 1 year with Z +2.7, had complex congenital heart disease and a paternal duplication [8]. Subject 36 (Z +2.4, ADHD) had a complex rearrangement, a distal duplication with deletion of the TAR region, inherited from the mother and present in two equally affected siblings, all photographed in Figure 3; it is an example of two CNVs of the same region in the same patient (section 2.7) [8].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis of carriers of 1q21.1 CNVs ranges from no manifestations to mild ID with psychiatric comorbidities and malformations, and depends more on each person's phenotype than on the type of CNV. The sources consulted do not include population-based data on life expectancy or mortality. The available prognostic information comes from four types of studies, which measure different outcomes and apply to different populations.

In proband series, which overestimate severity, most children with a distal deletion have mild delay and about 25% have mild ID or lifelong learning difficulties [1]. The most serious medical complications are cardiac: in the Turkish paediatric cohort of 42 children followed between 2019 and 2025, heart disease affected 34.5% of deletion carriers and two children with a distal deletion died from severe cardiac complications during follow-up [56]. Epilepsy, congenital cataracts and hearing loss determine functional prognosis when present [1].

In family cohorts, psychiatric risk persists into adulthood. In the Linden cohort, adults with a distal duplication had more psychiatric (73% vs 28%; OR 6.0), mood (55% vs 9%; OR 8.3) and anxiety (55% vs 16%; OR 10.0) disorders than family controls, and so did adults with a distal deletion (OR 4.0 for any psychiatric disorder and 6.0 for mood disorders), although adults with the duplication did not differ from controls in IQ [55]. The distal deletion increases the risk of schizophrenia about 8-fold (OR 8.35) [68]. In the population-based Danish iPSYCH cohort, schizophrenia risks were generally lower than in case-control studies, and diagnostic trajectories were similar for the deletion and the duplication [71].

In unascertained adults from the general population, the effect is small: UK Biobank distal deletion carriers had worse results in 7 of 11 cognitive and functioning measures (educational attainment, occupation, income, deprivation), with a mean effect of −0.27 on the cognitive tests; distal duplication carriers in 5, with a mean effect of −0.08 [21]. The penetrance of each CNV correlated with the mean number of children of carriers (r 0.78), and schizophrenia and autism risk CNVs altered fecundity in Iceland [21, 77]. In the same biobank, the 1q21.1 duplication was associated with diabetes, with an OR that increased after adjustment for BMI [38]. These data indicate that a carrier identified through cascade testing or by chance, without manifestations in childhood, has on average adult functioning slightly below that of the population, with a greater difference in the distal deletion than in the duplication, and an increased risk of psychiatric disorders whose individual magnitude is not predictable.

11.2. Surveillance

Table 22. Recommended surveillance.

The intervals in Table 22 are those of GeneReviews for the distal deletion, applicable to the distal duplication with the same adaptations as in Table 13 [1]. Psychiatric surveillance in adolescence and adulthood and metabolic surveillance in the duplication derive from the cohort data of Linden and Crawford, which do not define intervals [38, 55]; cardiac assessment of all carriers is a recommendation of the authors of the Turkish cohort [56]. In the proximal duplication, whose ID penetrance is 1.0%, surveillance should be directed at the phenotype present and does not, by itself, justify the full programme [6, 10]. For adult carriers identified through cascade testing without manifestations, the sources do not describe a specific surveillance programme, beyond reproductive counselling and attention to mental health [1].

12. Summary and Concluding Remarks

Band 1q21.1 contains four blocks of segmental duplications (BP1–BP4) which, through non-allelic homologous recombination, generate a class of recurrent CNVs: the distal BP3–BP4 deletion and duplication (class I), the extended BP1/BP2–BP4 CNVs (class II) and the proximal BP2–BP3 deletion and duplication, which contain RBM8A. The distal deletion (OMIM #612474) and the distal duplication (OMIM #612475) are neurodevelopmental susceptibility loci with incomplete penetrance and variable expressivity, with ClinGen scores of haploinsufficiency 3 and triplosensitivity 2; the proximal deletion only has an established clinical expression as the null allele of TAR syndrome, and the proximal duplication has weak evidence of pathogenicity (TS 1) and an ID penetrance of 1.0%.

The feature that best distinguishes the two distal CNVs is the mirror effect on head and brain size, with microcephaly in the deletion and macrocephaly in the duplication, in which CHD1L emerges in recent models as the main determinant. The deletion is associated with mild delay, mild ID in about a quarter of cases, cataracts and other ocular anomalies, seizures, short stature, congenital heart disease and a risk of schizophrenia about 8 times higher than that of the population; the duplication is associated with ASD, ADHD, developmental delay, tetralogy of Fallot and scoliosis. The frequencies of each feature vary with the mode of ascertainment, and family and population cohorts show that many carriers have development and adult functioning within the normal range.

Diagnosis is by chromosomal microarray, first line in developmental delay, ID, ASD and multiple congenital anomalies, and the report should state the breakpoints, gene content and ACMG/ClinGen classification, which considers the distal CNVs pathogenic despite reduced penetrance. Parental testing is recommended: the distal deletion is de novo in 18–35% of probands, the duplication is inherited in most cases, often from a parent without manifestations, and the proximal duplication is almost always inherited. A severe or atypical phenotype justifies a search for a second diagnosis by exome or genome sequencing.

Penetrance estimates depend on the outcome: 36.9% and 29.1% for any phenotype prompting a microarray (Rosenfeld 2013), 10% and 4.2% for ID with the Goh formula (2026). In counselling, the 50% transmission risk per pregnancy from a carrier parent is accompanied by the impossibility of predicting the phenotype, and the recurrence risk after a de novo CNV is below 1%. Prenatal diagnosis and preimplantation genetic testing are possible, but the prenatal finding does not predict the phenotype, and there is an authors' proposal not to report prenatally CNVs with penetrance close to 0%, a group that includes the proximal duplication and does not include the distal CNVs.

There is no targeted treatment, authorised drug or interventional trial. Management follows the GeneReviews recommendations: initial assessment of growth, development, eyes, hearing, heart, nervous system, genitourinary tract and behaviour, supportive treatment by specialty and surveillance at each visit, with ophthalmological and audiological assessment at least annually in childhood. Attention to mental health should continue through adolescence and adulthood, and genetic counselling should be repeated before reproductive age. Population-based data come mainly from the United Kingdom, Iceland and Denmark, and the sources consulted do not include data from Portugal or Brazil.

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