15q13.3 Microdeletion and Microduplication

Recurrent copy number changes in the 15q13.3 region, mediated by segmental duplications between breakpoints BP3, BP4, D-CHRNA7 and BP5, conferring susceptibility to intellectual disability, epilepsy, autism spectrum disorder and schizophrenia, with incomplete penetrance and variable expressivity; includes biallelic deletions and the recessive OTUD7A-associated disorder.

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From conventional cytogenetics to neurosusceptibility loci

15q13.3 recurrent deletion belongs to the group of copy number variants (CNV, copy number variants) that became visible only with microarray comparative genomic hybridisation. Before microarrays, a CNV inherited from a parent without the same phenotype was usually considered benign and a de novo change supported pathogenicity; recognition of several recurrent microdeletions and microduplications, more frequent in children with neurodevelopmental disorders but often inherited from an apparently normal parent, led to the concept of “predisposing” or neurosusceptibility loci with incomplete penetrance and variable expressivity [19]. Until 2008, some microarray platforms did not cover the 15q13.3 region, and older bacterial artificial chromosome (BAC) or low-density oligonucleotide platforms may not have detected the deletion, so results before that date do not exclude it [1].

1.2. Founding description and association milestones

The syndrome was described by Sharp, Mefford and colleagues in 2008 in Nature Genetics, from nine affected individuals in six families with intellectual disability, epilepsy and variable facial and digital dysmorphism. In one proband, the deletion began near BP3, adjacent to the Prader-Willi/Angelman region, and extended 3.95 Mb to BP5; in the others it corresponded to the smaller 1.5 Mb recurrent deletion between BP4 and BP5, containing six genes, including CHRNA7, immediately proposed as a seizure candidate. The estimated frequency in tested people with intellectual disability was approximately 0.3% (6/2 082), comparable to Williams, Angelman and Prader-Willi syndromes, and there were no deletions in 960 controls. The authors also observed that the BP4–BP5 region undergoes a common inversion, a possible predisposing factor for deletion [6, 20].

That same year, two large studies published in Nature associated the deletion with schizophrenia. The International Schizophrenia Consortium compared 3,391 patients with 3,181 ancestry-matched controls and found a 1.15-fold increased burden of rare CNV larger than 100 kb, with new associations with large deletions at 15q13.3 and 1q21.1 [21]. Stefansson and colleagues, starting from 66 de novo CNV identified in 9,878 transmissions, tested candidate regions in phase I with 1,433 cases and 33,250 controls and phase II with 3,285 cases and 7,951 controls, and associated 1q21.1, 15q11.2 and 15q13.3 deletions with schizophrenia and related psychoses; variants had arisen independently in several founders and were subject to negative selection [22]. In 2009, Helbig and colleagues found the deletion in 12 of 1,223 people with idiopathic generalised epilepsy (IGE) and none of 3,699 controls (p = 5.32 × 10⁻⁸), most with common epilepsy syndromes without intellectual disability, autism or schizophrenia, and termed it the most prevalent risk factor for common epilepsies identified to that date [23]. ClinGen curation transcribes this study's control denominator as 3,669; the article abstract states 3,699.

Ben-Shachar and colleagues described the deletion in 2009 as an incompletely penetrant locus for autism, intellectual disability and psychiatric disorders [24], and van Bon and colleagues delineated a clinical spectrum ranging from apparently non-pathogenic to severe, including the reciprocal duplication [25]. Shinawi and colleagues identified that same year a smaller recurrent deletion nested within 15q13.3, mainly encompassing CHRNA7 (now designated D-CHRNA7–BP5) [26], and Szafranski and colleagues characterised common duplications involving CHRNA7, whose pathogenicity remained uncertain [27]. Lowther and colleagues published a systematic review of 246 cases in 2015 and corrected phenotypic frequencies for ascertainment bias [7]; Gillentine and Schaaf reviewed phenotypes of all CHRNA7 copy number changes that same year [3]. In 2018, two independent studies identified OTUD7A as a critical gene for neurodevelopmental phenotypes [28, 29], and Gillentine and colleagues estimated population prevalence at approximately 1/5 525 [9]. The 2021 Norwegian population estimate and reformulation of penetrance published in 2025–2026 changed interpretation of individual risk, as discussed in sections 2 and 9 [10, 12].

1.3. Nomenclature and definition of entities within scope

GeneReviews uses “15q13.3 recurrent deletion” specifically for the heterozygous ~2.0 Mb deletion between BP4 and BP5 (approximately 30.5–32.5 Mb in GRCh37), with 1.5 Mb unique sequence and at least 500 kb of segmental duplications; it does not include deletions outside these coordinates or biallelic deletions, whose phenotype is clinically distinct [1]. Differences between sizes reported in the literature (1.5 Mb, ~2.0 Mb, 1.3–1.4 Mb) result from whether segmental duplications are included and the probe density of each platform; ClinGen defines the region by the unique sequence between BP4 and BP5 and considers deletions extending to BP3 functionally equivalent [6]. Orphanet defines the entity as a rare chromosomal anomaly with high risk of a broad range of neurodevelopmental disorders, including global developmental delay, intellectual disability and behavioural problems of variable severity, emphasising that the microdeletion does not produce a clinically specific phenotype [2].

In this article, BP4–BP5 deletion designates the main recurrent form; BP3–BP5 deletion is the larger form (~3.4–3.95 Mb, more than 20 genes), accounting for the minority of deletions in the region, since BP4–BP5 accounts for ~94% [1]; D-CHRNA7–BP5 deletion is the small nested form (~350–700 kb), with breakpoints in the D-CHRNA7 repeat proximal to CHRNA7, encompassing CHRNA7 with or without the first OTUD7A exon [3, 4]. Biallelic deletion designates loss of both copies of part of the region, through homozygosity for the same deletion or compound heterozygosity for deletions of different sizes. Microduplication designates the reciprocal BP4–BP5 or BP3–BP5 gain and, separately, D-CHRNA7–BP5 duplication, which is much more frequent in the population; CHRNA7 triplication has been described in a single family [3]. The recessive OTUD7A-related disorder (NEDHS, neurodevelopmental disorder with hypotonia and seizures, OMIM 620790) is an allelic disorder of a gene within the interval, which may arise through biallelic sequence variants or a 15q13.3 deletion in trans with a pathogenic variant on the remaining allele [8].

2. Molecular Genetics and Pathophysiology

2.1. Genomic architecture of the 15q11–q14 region

The proximal long arm of chromosome 15 has a high density of low-copy repeats (LCR, low-copy repeats), or segmental duplications, making it susceptible to genomic rearrangements causing partial aneuploidy; six breakpoints (BP1 to BP6) have been characterised in 15q11q14, and rearrangement breakpoints cluster in these LCR. The same architecture explains Prader-Willi and Angelman deletions (BP1 or BP2 to BP3), dup15q and 15q11.2 changes (BP1–BP2), which lie outside this article's scope and appear only as differential diagnoses [1]. 15q13.3 recurrent deletion forms through non-allelic homologous recombination (NAHR, non-allelic homologous recombination) between BP4 and BP5 LCR when they are in direct orientation, a configuration generated mainly by a common BP4–BP5 inversion [1, 20]. The Oxford reference describes the mechanism as “non-homologous recombination”, an imprecise formulation; the accepted mechanism is NAHR, producing reciprocal deletions and duplications [1, 19].

Antonacci and colleagues showed that at least five human structural configurations of the region (2–3 Mb) exist, arising approximately 0.5–0.9 million years ago through expansions of human-lineage-specific segmental duplications and two independent inversions. Inversion and recurrent microdeletion breakpoints map near ~14 kb duplicated GOLGA8 cores organised in palindromes, with significant clustering (p = 0.002) [30]. Small deletions and duplications use LCR in the D-CHRNA7 repeat proximal to CHRNA7, with breakpoints between OTUD7A exons 1 and 2; at least six NAHR hotspots and five classes of small CHRNA7 duplications have been described. The chimeric fusion gene CHRFAM7A (CHRNA7 fused with FAM7A) shares exons 5 to 10 with CHRNA7 and increases local homology [3].

A March 2026 preprint, not yet peer reviewed, used long-read genome assemblies in 10 patient-parent trios and 581 control haplotypes of diverse ancestries. Long (BP4–BP5) and short (CHRNA7) CNV arose predominantly through NAHR promoted by large inversion polymorphisms; three BP4–BP5 breakpoints clustered in a 2 kb recombination hotspot enriched in PRDM9 motifs; at least 18 structural haplotypes were identified, most CNV were structurally distinct and affected ARHGAP11B and CHRFAM7A differently, and the predisposing haplotype was present in 68.4% of European haplotypes and 5.1% of East Asian haplotypes, potentially stratifying BP4–BP5 CNV risk more than tenfold by ancestry [31]. These data have not yet been confirmed in a peer-reviewed publication.

2.2. Genes within the interval and their functions

For each gene, the table gives the MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript; AD denotes autosomal dominant and AR autosomal recessive inheritance.

Coordinates and MANE transcripts were obtained from Ensembl for GRCh38 [5]. GeneReviews lists six known genes for the BP4–BP5 deletion (FAN1/MTMR15, TRPM1, MTMR10, KLF13, OTUD7A and CHRNA7) and mentions ARHGAP11B among genes in the region [1]; the homozygous case described in section 10 also includes MIR211 and ARHGAP11A in the deleted interval, which varied with breakpoints [34].

2.3. Disease mechanism: contiguous gene haploinsufficiency

How loss of one copy of the interval causes the phenotype is unknown, and no single gene has been associated with the full presentation [1]. Smaller deletions encompassing only CHRNA7 and the first OTUD7A exon have been found in individuals with developmental delay, intellectual disability, autism spectrum disorder (ASD), epilepsy and schizophrenia, implicating one of these two genes as the likely cause of neuropsychiatric manifestations [1, 35].

CHRNA7 encodes the nicotinic receptor α7 subunit, a synaptic ion channel mediating neuronal transmission; nicotinic receptors are ligand-gated channels formed from five subunits [1, 8]. No individual with a disease-causing loss-of-function CHRNA7 variant has been described [1]. Gene analysis is complicated by duplication of exons 5 to 10 and the 3' untranslated region in CHRFAM7A, making sequencing of the shared region poorly informative; CHRFAM7A, including the CHRFAM7AΔ2bp polymorphism, has been proposed as a modifier with possible dominant-negative effects on α7 receptors in Xenopus oocyte and cell-line studies [3]. ClinGen classifies the D-CHRNA7–BP5 region as having emerging evidence of haploinsufficiency and considers CHRNA7 a proposed candidate gene without established haploinsufficiency [4].

OTUD7A encodes a deubiquitinating enzyme located in dendritic spines of cortical neurones. Uddin and colleagues combined genomic sequencing, human brain proteome and transcriptome and the Df(h15q13)/+ mouse, showing that microdeletion causes abnormal cortical dendritic spine development and dendritic growth [28]. Yin and colleagues described mice lacking Otud7a with reduced weight, developmental delay, abnormal electroencephalogram (EEG) and seizures, fewer ultrasonic vocalisations, reduced grip strength, learning and motor coordination deficits, reduced acoustic startle, lower spine density and lower miniature excitatory postsynaptic current frequency in frontal cortex, concluding that reduced OTUD7A dosage is a major contributor [29]. Kozlova and colleagues showed in human neurones that OTUD7A loss of function, in the context of schizophrenia-associated deletion, impairs synaptic development and function, and described loss-of-function OTUD7A variants in people with schizophrenia [1, 32].

Recent research has added hypotheses that remain preclinical. Human forebrain assembloids derived from microdeletion carriers showed early gene-network dysregulation in cortical neurones, migration deficits, fewer synaptic connections and reduced activity in inhibitory subpopulations, with hyperactive, hyperconnected networks and increased DNA damage in inhibitory neurones, which the authors relate to FAN1 (preprint) [36]. In Df(h15q13)/+ mice, peripheral immune stimulation with lipopolysaccharide (0.1 mg/kg) or Poly(I:C) (5 mg/kg) increased hippocampal CXCL2 expression up to 200-fold and CXCL10 up to 600-fold, with genotype × treatment interactions for CXCL2, TLR3, TLR4, HMGB1 and C1qA [37]. These data have no established clinical translation.

2.4. Inheritance pattern and parental origin

The deletion is transmitted in an autosomal dominant manner; approximately 85% are inherited and approximately 15% arise de novo [1]. In Lowther's review, inheritance was demonstrated in 85.4% of cases with known origin, which was disproportionately maternal (p < 0.0001) [7]; in Gillentine and Schaaf's review, with origin known in 87 of 208 carriers, 18 deletions were de novo and 69 inherited, 57.5% from an unaffected parent and 21.8% from an affected parent, and CHRNA7 deletions were significantly more often maternally transmitted (p < 0.0001), mainly driven by BP4–BP5 deletions [3]. ClinGen summarises that approximately 80% of BP4–BP5 deletions are inherited and approximately 75% of inherited deletions come from an apparently unaffected parent [6]. These values derive from cases ascertained through a phenotype; in an unselected Norwegian newborn cohort, one of five deletions was de novo [10]. The sources consulted do not explain the predominance of maternal transmission.

2.5. Genotype–phenotype correlations between entities within scope

GeneReviews recognises no genotype–phenotype correlations within BP4–BP5 deletion: the same rearrangement ranges from normal phenotype to substantial impairment, and no clinically relevant differences have been described between BP3–BP5, BP3–BP4 and BP4–BP5 deletions [1]. Small D-CHRNA7–BP5 deletions produce phenotypes similar to BP4–BP5 and BP3–BP5 deletions [1, 3], but ClinGen assigns them weaker haploinsufficiency evidence because they are few and more frequently inherited from a clinically affected parent [4]. Comparison between classes in aggregate data suggests deletions are more associated with seizures and duplications with ASD, attention deficit hyperactivity disorder (ADHD), mood disorders and schizophrenia, but these data suffer from ascertainment bias [3]. Biallelic deletions produce a consistent severe presentation (section 3.6), and retinal involvement depends on inclusion of TRPM1 in both lost copies [3, 33].

2.6. Penetrance and expressivity

Penetrance must be interpreted according to method. The proportion of 80.5% of published cases with at least one neuropsychiatric or neurodevelopmental diagnosis describes an ascertained population, not the probability of a carrier in the general population becoming affected [1, 7]. Kirov and colleagues, using a method integrating frequencies in controls (0.019%), schizophrenia (0.14%) and developmental delay, ASD or congenital malformations (0.26%), and an estimated general population frequency of 0.03%, calculated deletion penetrance of 4.7% (95% CI 2.2–9.9) for schizophrenia, 35% (19–62) for developmental delay, ASD or malformations, and 40% (21–72) for any of these phenotypes; the estimated selection coefficient was 0.31 [11]. Rosenfeld and colleagues did not estimate BP4–BP5 deletion penetrance because they found none in 22,246 controls, which would give an artificial 100% value despite cases inherited from healthy parents; thus the penetrance table reproduced in reference works has no 15q13.3 row [19, 38].

Goh and colleagues proposed in 2025 a definition of penetrance as the probability of manifesting the phenotype because of the variant, excluding population background risk. With 87 BP4–BP5 deletions in 33,010 affected people from eight studies and 27 in 269,885 gnomAD v4.0 controls, and a paediatric intellectual disability prevalence of 1.1% in high-income countries, deletion penetrance for intellectual disability was 22% (95% CI 15–31) under the new formula versus 59% (48–69) under the previous method with the same data; for BP4–BP5 duplication (27/32 587 versus 140/269 885), it was 0.7% (0.0001–1.4) versus 7.9% (5.1–11). The authors did not estimate small CHRNA7/OTUD7A CNV because of data complexity, the analysis is restricted to a single phenotype (intellectual disability) and does not cover epilepsy, schizophrenia or ASD, and they advise caution because of coordinate complexity [12]. ClinGen incorporated these estimates into its February 2026 reassessment [6].

Expressivity varies greatly within the same family. When phenotype differs between parent and child with the same CNV, considerations include unmasking a recessive allele on the homologous chromosome, incomplete penetrance, complex inheritance involving other genetic and environmental factors, amplification of a duplication (duplication to triplication) and extension of a deletion [19]. A second CNV is frequent: 5 of 18 patients (28%) assessed by Ziats had another CNV of uncertain significance [6, 39], and 5 of 16 children with CHRNA7 duplication had a second CNV, one being a 22q11.2 deletion [4, 40]. Smith's reference places these reciprocal CNV (1q21.1, 15q11.2, 15q13.3, 16p11.2) in a multifactorial model, with markedly low penetrance in vertical transmission and unknown interaction with other factors [41]. In the adult UK Biobank population, neurodevelopmental CNV carriers without a neurodevelopmental diagnosis have modest cognitive deficits and greater medical morbidity (diabetes, hypertension, obesity, renal failure) and internalising-cardiometabolic multimorbidity, in aggregate analyses whose 15q13.3-specific values are absent from the portions read [42–45].

2.7. Allelic disorders and recessive unmasking

Recessive OTUD7A-related disorder (NEDHS). This is characterised by global developmental delay, language impairment, intellectual disability, hypotonia and early-onset seizures [8]. The first patient, described by Garret and colleagues, was homozygous for the variant NM_130901.2:c.697C>T p.(Leu233Phe) (transcript of the original publication), at an ultraconserved amino acid in the catalytic OTU domain, and had severe global delay, language impairment and epileptic encephalopathy; the parents, who had learning difficulties, and one sibling were heterozygous, and proteasome formation and function were reduced in patient fibroblasts and in OTUD7A-deficient HAP1 cells [46]. On the MANE Select transcript the variant is described as NM_001382637.1:c.697C>T, NP_001369566.1:p.(Leu233Phe), corresponding to NC_000015.10:g.31527264G>A in GRCh38 and NC_000015.9:g.31819467G>A in GRCh37; historical transcript NM_130901.2 is currently version NM_130901.3 [47]. Suzuki and colleagues described a patient with profound hypotonia, severe intellectual disability and seizures who had a de novo 15q13.3 deletion in trans with a de novo OTUD7A frameshift variant [8, 48]; other cases were identified by sequencing the non-deleted allele in recurrent deletion carriers (Yuan and colleagues, 2022, cited by GeneGuidance) [8]. ClinGen classified the relationship of OTUD7A with autosomal recessive complex neurodevelopmental disorder as “limited” (June 2023) and PanelApp Australia as “moderate”; an isolated heterozygous OTUD7A sequence variant has no established dominant significance, and ClinGen assigns the isolated gene haploinsufficiency and triplosensitivity scores of 0 [8].

Complete congenital stationary night blindness (TRPM1). Biallelic TRPM1 loss causes complete Schubert-Bornschein-type cCSNB, with an electronegative electroretinogram (ERG) (preserved a-wave and markedly reduced or absent scotopic b-wave), nystagmus, often high myopia, reduced acuity and strabismus, without progression; in the original report, 10 of 38 CSNB patients had TRPM1 variants [8]. In biallelic 15q13.3 deletions including TRPM1, retinal involvement is constant (section 3.6) [33]. Melanoma-associated retinopathy with anti-TRPM1 antibodies is acquired, not genetic [8].

Karyomegalic interstitial nephritis (FAN1). This is a rare autosomal recessive disease (prevalence < 1/1 000,000; 2026 ClinGen curation with 56 families, 122 individuals from 22 countries and 38 pathogenic or likely pathogenic variants), with chronic kidney disease typically from the third decade, end-stage kidney disease often before 50 years and mild or absent proteinuria. A heterozygous 15q13.3 deletion carrier is a FAN1 carrier, not a patient with karyomegalic interstitial nephritis, and the deletion phenotype is not attributed to FAN1; the relationship of FAN1 with Lynch syndrome is “limited”, and the gene modifies age at onset in Huntington disease [8].

Congenital heart disease (KLF13). ClinGen classified in February 2024 the relationship of KLF13 with autosomal dominant congenital heart disease as “moderate”, based on rare variants in patients with heart disease, for example NM_015995.4:c.487C>T p.(Pro163Ser) in a patient with tricuspid atresia, c.467G>A p.(Ser156Asn) in a patient with transposition of the great arteries (2 of 309 patients, 0 of 200 controls) and c.370G>T p.(Glu124Ter) in a Chinese family with double-outlet right ventricle and ventricular septal defect [8, 47]. These variants correspond in GRCh38 to NC_000015.10:g.31327699C>T, g.31327679G>A and g.31327582G>T, with identical numbering in versions NM_015995.3 and NM_015995.4 [47]. KLF13 haploinsufficiency is only a hypothesis for the approximately 3% of deletion carriers with structural heart disease; the sources do not establish this causality [1, 8].

GeneGuidance also notes that ClinVar TRPM1 variant counts are inflated by 15q13.3 CNV records and that ORPHA:199318 prevalence does not apply to cCSNB [8].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and data sources

Manifestations of heterozygous deletion are highly variable; the deletion may not produce a recognisable syndrome, and a subset of carriers has no evident clinical findings, including developmental or cognitive delay. Congenital malformations are uncommon [1]. More than 200 individuals with the recurrent deletion have been published [1]. Phenotypic frequencies come from series ascertained through a phenotype, predominantly developmental delay or intellectual disability, overestimating manifestations; GeneReviews and Lowther corrected this bias, and the following tables distinguish adjusted from raw values [1, 7]. None of the cohorts describes evolution under a specific therapy, which does not exist; the data represent natural history with usual symptomatic treatment.

Sources: [1, 3, 6, 7]. The high 51% value for behavioural findings comes from a report excluding publications with fewer than three individuals and not correcting ascertainment bias [1]. Individuals with developmental delay or intellectual disability are more likely to undergo microarray testing, which is why raw values overestimate frequency [1, 39].

3.2. Development and cognition

Delays predominantly affect speech acquisition and cognitive function rather than motor skills; hypotonia may contribute to mild motor delays. Most have mild cognitive impairment, and a subset has moderate to severe intellectual disability [1, 7, 24, 25]. Ziats and colleagues systematically assessed 18 individuals (15 with BP4–BP5 and 3 with BP3–BP5 deletion; 14 male), with mean verbal intelligence quotient (IQ) of 64.3 and non-verbal IQ of 60.1, without a significant difference between them, documenting intellectual disability or developmental delay, ASD, hyperactivity, attention problems, epilepsy and hypotonia [1, 6, 39]. Hypotonia is generally mild and improves during childhood; independent walking occurs between 12 months and 3 years (mean 21.5 months) [1]. In Ben-Shachar's series (20 individuals from 12 families, identified through routine microarray), phenotypes included developmental delay, intellectual disability, ASD, speech delay, aggression and ADHD, with normal to moderately dysmorphic facial features; two carrier parents had learning difficulties and bipolar disorder, and four carrier parents were unaffected [6, 24].

3.3. Epilepsy

Approximately 30% of carriers have epilepsy [1, 7, 49]. The deletion is a recognised risk factor for common generalised epilepsies without intellectual disability: in Helbig's series, 9 of 12 IGE probands had neither dysmorphism nor intellectual disability, and inheritance was demonstrated in 4 of 5 with known origin (one parent with panic disorder and the others unaffected) [6, 23]. The 15q13.3 deletion, together with 15q11.2 and 16p13.11, is among recurrent microdeletions associated with seizures and intellectual disability in the childhood epilepsy differential; a reference work attributes approximately 3% of primary generalised epilepsies to this group of microdeletions, without giving a denominator [50, 51].

Whitney and colleagues reviewed, at a single Canadian centre, 13 children with 15q13.3 microdeletion and epilepsy (69% girls; median age 12 years, range 3–15). Median seizure onset was 4 years, and 11 (85%) had intellectual disability. Nine (69%) had typical absences, with median onset at 5 years, two with absence status epilepticus; four (31%) had focal non-motor impaired-awareness seizures; six (46%) fulfilled criteria for an absence epilepsy syndrome recognised by the International League Against Epilepsy (ILAE), and the remainder had genetic generalised epilepsies with overlapping features, combined or focal epilepsies. EEG showed generalised discharges in 85%, focal discharges in 62% and posterior dominant rhythm slowing in 33%, and one child had electrical status epilepticus in sleep; one-third were drug-resistant [14]. GeneReviews summarises that absences begin in childhood and may have atypical features (early onset, persistence into adolescence, absence status epilepticus and treatment resistance), rarer generalised types such as myoclonic absences and atonic seizures occur, and EEG may combine generalised and focal findings [1]. In the 2013–2024 Polish paediatric cohort, 4 of 13 children with 15q13.3 deletion had epilepsy; one child with 15q13.3 deletion and 1q21.1 duplication did not have epilepsy [52]. Antiseizure medication response is discussed in section 7.

3.4. Behaviour and psychiatry

Approximately one-third of carriers have behavioural or psychiatric findings: ASD, ADHD, mood disorder, self-injury, aggressive or impulsive behaviour [1, 7]. Schizophrenia occurs in approximately 11% of adults with the deletion after ascertainment-bias correction, and the deletion is enriched in schizophrenia cohorts in three studies [1, 7, 21, 22]. Kirov's estimated schizophrenia penetrance in the carrier population is 4.7% (95% CI 2.2–9.9), much lower than the 11% of ascertained adults, showing that most phenotypically affected carriers manifest early-onset disorders [11]. A 39-year-old man with 15q13.3 deletion, epilepsy, intellectual disability, psychosis and recurrent episodes of aggressive rage illustrates overlapping adult manifestations [53]. Deletion frequency in people with ASD is low: rare CNV explain 5–10% of ASD cohorts, the most common being 16p11.2 (~0.5%), and 15q13.3 belongs to the group of identifiable rare CNV [54].

3.5. Other systems

Brain magnetic resonance imaging (MRI) is rarely abnormal; arachnoid cysts, cerebellar vermis hypoplasia, ventricular dilatation, corpus callosum agenesis, focal cortical dysplasia and heterotopia have been reported, alongside non-specific findings such as mild prominence of extracerebral spaces, focal volume loss, prominent cerebellar folia and subcortical white matter T2 hyperintensities [1, 14]. There is no specific dysmorphism or recognisable facial appearance; when present, dysmorphic features are non-specific [1, 49]. Structural congenital heart disease occurs in approximately 3%, and occasional hypercholesterolaemia has been described. Ocular abnormalities affect 6% (Pavone 2020), predominantly strabismus and astigmatism. Hearing is generally normal, with transient hearing loss from recurrent otitis in childhood. Growth is normal in most, although short and tall stature have been described [1]. Whether gastrointestinal (gastro-oesophageal reflux, hiatus hernia, diverticulosis), endocrine (hypothyroidism, diabetes with insulin resistance) and urogenital abnormalities (renal cyst, urethral stenosis, nephrolithiasis) are rare findings or co-occurrences remains uncertain. Placenta praevia occurred in 1.6% of pregnancies in proband mothers, up to five times the general population estimate, a signal requiring study with control of confounders [1, 7]. In Młynek's series, a boy with a de novo deletion had psychomotor delay, seizure-like episodes with unresponsiveness, joint laxity, significant myopia, amblyopia, strabismus and nystagmus [52].

3.6. Larger BP3–BP5 deletion and small D-CHRNA7–BP5 deletion

The BP3–BP5 deletion (3.4–3.95 Mb, more than 20 genes) was reviewed in 14 heterozygotes: origin was known in seven (four de novo, two from an affected mother and one from a neurotypical mother), and there was also an unaffected father of a child with a homozygous deletion. Among 12 affected individuals, nine (75%) had cognitive impairment, eight (66.7%) language disorder, five (41.7%) seizures or abnormal EEG, five (41.7%) ADHD, three (25%) ASD, five (41.7%) abnormal behaviours including a Prader-Willi-like phenotype with hyperphagia, five overweight or obesity, seven (58.3%) mild dysmorphism and four (33.3%) hypotonia [3]. Pavone and colleagues described an Italian family of four (mother and three children) and an unrelated boy with BP3–BP5 deletion (arr[hg19] 15q13.1q13.3(29213402_32510863)×1), in whom speech delay and language disorder were typical signs, proposing the region as a language disorder locus [49]. GeneReviews recognises no significant clinical differences between BP3–BP5 and BP4–BP5 deletions [1].

D-CHRNA7–BP5 deletions were reviewed in 42 carriers, 37 with a neurological phenotype: cognitive impairment in 19 (51.4%), seizures or abnormal EEG in 13 (35.1%), dysmorphism in 9 (24.3%), ASD in 6 (16.2%), ADHD in 5 (13.5%), language disorder in 5 (13.5%), mood disorder in 4 (10.8%), hypotonia in 4 (10.8%) and schizophrenia in 1 (2.7%). Inheritance was known in 19 (one de novo and 18 inherited), and in eight independent cases carrier parents were affected in six [3, 4]. Shinawi described 10 individuals from four families with mild to severe intellectual disability, global delay and abnormal EEG or seizures, with one carrier mother having mild intellectual disability without seizures, another epilepsy with normal cognition and a maternal grandmother mild intellectual disability [4, 26]. Hoppman-Chaney described 19 individuals from nine families with developmental delay or cognitive impairment and ASD, including a 9-month-old infant tested for mild hypertelorism and chronic otitis with normal development, and inheritance from parents with psychiatric or behavioural conditions in four of five with known origin [4, 35]. In Coe's case-control study, D-CHRNA7–BP5 deletion occurred in 12 of 29,085 children with developmental delay and none of 19,584 controls (p = 0.002) [4, 55].

3.7. Biallelic deletions

Biallelic deletions produce a severe consistent phenotype: neonatal-onset encephalopathy, hypotonia, intellectual disability, cortical and retinal visual impairment, optic nerve abnormality, epilepsy and abnormal EEG [1, 34]. In Gillentine and Schaaf's review of 11 cases (three compound heterozygotes — one BP4–BP5/BP3–BP5 and two BP4–BP5/D-CHRNA7–BP5 —, two D-CHRNA7–BP5 homozygotes and six BP4–BP5 homozygotes), cognitive impairment and hypotonia were present in 11/11, other neurological conditions in 10 (91%; abnormal MRI, areflexia, subarachnoid cysts, dysmorphic corpus callosum), seizures or abnormal EEG in 9 (81.8%), language disorder in 9 (81.8%), ASD in 1 (9.1%) and ocular pathology in 8 (72.7%), all with homozygous deletions of at least 1.5 Mb including TRPM1, versus 6% of heterozygotes [3]. In Simon's table of 12 patients, hypotonia and developmental delay occurred in 12/12, visual impairment in 11/12 (one without data), abnormal optic nerve in 6/9, abnormal ERG in 5/6, abnormal EEG in 10/11 and seizures in 8/10, frequently refractory; MRI ranged from normal to arachnoid cysts, dysmorphic corpus callosum, frontal atrophy or dysplastic cerebellum, and one patient died at 13 years [34]. Masurel-Paulet described three French patients (30 months to 9 years, including two siblings) with classical homozygous 1.5 Mb deletion, congenital blindness and epileptic encephalopathy with inconsistent abnormal movements, absent visual tracking, optic nerve pallor, immature visual evoked potentials and retinal dystrophy with negative ERG (b-wave smaller than a-wave under scotopic bright-flash conditions) in all; the ocular phenotype was attributed to homozygous TRPM1 loss and neuronal ceroid lipofuscinosis identified as the main differential diagnosis [33]. Smaller homozygous deletions without TRPM1 lacked the retinal component, although visual tracking difficulty has been reported, and CHRNA7 may contribute to cortical visual impairment [34]. Most parents are healthy or have mild intellectual disability, learning difficulties or ADHD [34].

3.8. BP4–BP5 microduplication and CHRNA7 duplication

Reciprocal microduplication has been observed in people with intellectual disability, ASD and ADHD, with much lower penetrance than deletion [1, 25, 27, 56]. Because few cases have data beyond the ascertainment phenotype, the associated phenotype is uncertain; it includes intellectual disability, ADHD, behavioural problems, ASD, hypotonia, obesity and recurrent otitis, without dysmorphism, recurrent congenital anomalies or epileptic seizures in the GeneReviews summary; it may be de novo or inherited from an apparently unaffected parent [1]. Among 18 reviewed BP4–BP5 duplication carriers, 16 affected, cognitive impairment occurred in 7 (43.8%), ASD in 7 (43.8%), ADHD in 5 (31.3%), language disorder in 5 (31.3%), dysmorphism in 4 (25%), seizures or abnormal EEG in 3 (18.8%), mood disorder in 3 (18.8%) and schizophrenia in 1 (6.25%); inheritance was known in seven (five de novo and two from an unaffected parent) [3, 6]. One report described dysmorphism, developmental delay, intellectual disability, behavioural problems and ventricular and atrial septal defects in a child with duplication inherited from a phenotypically normal father [6]. ClinGen found no enrichment of BP4–BP5 duplication in clinical populations, noted a conflicting inheritance pattern and an effect on only one subclinical neurocognitive measure in general population carriers, and assigned little evidence for triplosensitivity [6].

D-CHRNA7–BP5 duplication is common: present in 0.2% of people in gnomAD-SV 4.1, it occurred in 161 of 29,085 children with developmental delay and 128 of 19,584 controls (likelihood ratio 0.847; 95% CI 0.687–1.04), without enrichment, and in UK Biobank, 3,023 adult carriers differed from non-carriers in only 1 of 11 measures (0 of 7 cognitive measures) [4, 43, 55]. In the Norwegian newborn cohort, all 14 nested duplications were inherited, which the authors interpreted as supporting phenotypic neutrality [10]. Clinical data in ascertained children differ: Gillentine and colleagues assessed 16 children with CHRNA7 duplication and found language disorder in 10/16, ADHD in 10/16, clinical impression of ASD in 6/15, seizures in 3/16 and hypotonia in 4/16; duplication was inherited in 15/16, 65% of carrier parents reported neuropsychiatric problems and five probands had a second CNV [4, 40]. In 67 reviewed cases with clinical data, no phenotype exceeded one-third (cognitive impairment and schizophrenia each 28.3%, ADHD and mood disorders 18.3%, ASD 15%) [3]. In childhood-onset schizophrenia, 2 of 136 probands had paternally inherited focal CHRNA7 duplications [4]. In an Alzheimer disease sample, small duplication occurred in 6 of 276 cases (2%) versus 1 of 332 controls (0.3%) [3]. Many laboratories now interpret CHRNA7-limited duplications as likely benign, and ClinGen considers dosage sensitivity unlikely [1, 4]. Kirov and colleagues likewise do not consider it pathogenic because it occurs at equal frequencies in cases and controls [11].

CHRNA7 triplication was described in a family of four with a complex rearrangement (DUP-TRP/INV-DUP): three had neuropsychiatric phenotypes (cognitive impairment, ASD, ADHD, mood disorder) and mild dysmorphism, the mother had seizures from 20 years and the maternal grandfather had alcohol and drug dependence [3].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the condition

Because there is no recognisable phenotype, the deletion is rarely suspected clinically and is almost always identified on microarray requested for developmental delay, intellectual disability or ASD [1]. GeneReviews suggests considering it in intellectual disability, speech delay, seizures, autism, schizophrenia, behavioural findings (attention deficit, hyperactivity, mood disorder, aggressive or impulsive behaviour) and particularly combinations of these manifestations, such as intellectual disability with seizures. Family history compatible with autosomal dominant transmission, with males and females affected across several generations, supports suspicion, but absence of family history does not exclude it [1].

4.2. Warning signs and emergencies

Absence status epilepticus, treatment resistance and seizure worsening after introducing a sodium channel blocker such as oxcarbazepine should prompt neurological reassessment [1, 14]. Emergence of psychotic symptoms in an adolescent or adult carrier requires psychiatric assessment, given the risk of late-onset schizophrenia [1]. In an infant with severe hypotonia, absent visual tracking and EEG slowing, biallelic deletion should be considered; in published cases, ERG documented the retinal component [33, 34]. There is no newborn screening for this condition.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria. Diagnosis is established in a proband by identifying the recurrent heterozygous ~2.0 Mb deletion at 15q13.3 through chromosomal microarray (CMA) or targeted methods [1]. BP4–BP5 deletion fully overlaps a region of established haploinsufficiency (ClinGen score 3), worth 1.00 point under criterion 2A in the American College of Medical Genetics and Genomics (ACMG)/ClinGen CNV classification system, leading to a pathogenic classification; the system itself accepts as pathogenic CNV with a consistent phenotype in multiple publications and well-documented penetrance, even if reduced or variable [6, 60]. A legacy BP4–BP5 deletion entry remains in ClinGen (ISCA-37479, awaiting review); the current curation is ISCA-37411 [6, 61]. D-CHRNA7–BP5 deletion (haploinsufficiency 2) and duplications require careful case-by-case assessment [4, 60].

5.2. Tests and sensitivity

Source: [1]. FISH, fluorescence in situ hybridisation; qPCR, quantitative polymerase chain reaction; MLPA, multiplex ligation-dependent probe amplification.

CMA is recommended as a first-line genomic test in people with unexplained developmental delay or intellectual disability, ASD or multiple congenital anomalies [13, 19]. SNP arrays also detect uniparental disomy and isodisomy and are more sensitive to mosaicism than comparative genomic hybridisation, although they poorly quantify the percentage of affected cells [19]. The 2021 ACMG guideline strongly recommends exome (ES) or genome sequencing (GS) as a first- or second-line test in paediatric patients with congenital anomalies beginning before 1 year or developmental delay or intellectual disability beginning before 18 years [62]. In epilepsy, the ILAE genetics commission recommends ES or GS with CNV analysis as first line in most cases, attributes 1.5–3% of common epilepsies and up to 16% of developmental and epileptic encephalopathies to CNV, and gives a CMA yield of 5–15%; in IGE (childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, generalised tonic-clonic seizures alone), testing is considered only with family history, intellectual disability, autism, dysmorphism or drug resistance [58]. The National Society of Genetic Counselors (NSGC) strongly recommends genetic testing for all people with unexplained epilepsy, without age limit, using ES/GS or a multigene panel (more than 25 genes) first line followed by CMA, with pre- and post-test counselling [63]. The International Society of Psychiatric Genetics (ISPG) considers CMA standard care for assessing global delay, intellectual disability or ASD, finds no consensus for CNV analysis in most adults with mental illness and acknowledges its value in atypical presentations or with intellectual disability, ASD, learning difficulties or certain medical syndromes [57].

5.3. Test limitations

A pre-2008 or low-density CMA may not have detected the deletion [1]. Next-generation sequencing permits CNV and single nucleotide variant detection in one test [58], but segmental duplications at breakpoints limit precise endpoint definition and distinction between different CNV classes, which differ structurally and variably affect ARHGAP11B and CHRFAM7A [3, 31]. CHRNA7 sequencing is poorly informative in the region shared with CHRFAM7A (exons 5–10 and 3' untranslated region), complicating searches for variants on the remaining allele [3]. Detecting a deletion does not exclude a second cause: 5 of 18 systematically assessed patients (28%) had another CNV [6]. When a patient with heterozygous deletion has a severe or recessive phenotype (epileptic encephalopathy, night blindness, kidney disease), sequencing the remaining allele (OTUD7A, TRPM1, FAN1) may reveal recessive unmasking [8, 19]. Leucocyte DNA may not detect all parental somatic mosaicism [1].

5.4. Report content

The report should give International System for Human Cytogenomic Nomenclature (ISCN) nomenclature with genome build and coordinates, for example arr[GRCh37] 15q13.2q13.3(30860236_32621188)×1 for a BP4–BP5 deletion and arr[GRCh37] 15q13.3(31940425_32444043)×3 for a D-CHRNA7–BP5 duplication [64], estimated size, class (BP4–BP5, BP3–BP5, D-CHRNA7–BP5), included genes, copy number and zygosity, classification into five ACMG/ClinGen categories (pathogenic ≥ 0.99 points; likely pathogenic 0.90–0.98; uncertain significance between −0.89 and 0.89; likely benign; benign) and recommendation for parental studies [60]. In the scoring system, a loss inherited from an apparently unaffected parent with a non-specific phenotype subtracts 0.15 points (range 0 to −0.30), and segregation with a consistent phenotype scores according to segregation criteria; laboratories may adopt context-specific practices, for example reporting prenatally only pathogenic or likely pathogenic variants associated with dominant conditions, and should document them [60]. When the report describes a sequence variant on the remaining allele, it should include gene, versioned transcript (for example NM_001382637.1 for OTUD7A), Human Genome Variation Society (HGVS) nomenclature, zygosity and ACMG/AMP (Association for Molecular Pathology) class [47].

5.5. Algorithm

1. Person with developmental delay, intellectual disability, ASD, multiple congenital anomalies, unexplained epilepsy with comorbidity or atypical psychiatric presentation: CMA or ES/GS with CNV analysis, according to availability and local guidelines [13, 58, 62, 63].
2. 15q13.3 deletion identified: classify by class and genes involved; consult ClinGen and DECIPHER for gene content, phenotypes and typical inheritance [6, 19].
3. Test parents with a method detecting the deletion; result inherited from an unaffected parent, affected parent or de novo; confirm in the proband by FISH, qPCR or MLPA if necessary [1, 19].
4. Phenotype more severe than expected or disproportionate to the carrier parent: consider a second CNV, a variant on the remaining allele (OTUD7A, TRPM1) or another monogenic diagnosis, and proceed with ES/GS [8, 19].
5. Isolated D-CHRNA7–BP5 duplication: generally likely benign; continue aetiological investigation [1, 4].

The Oxford reference, based on the Miller 2010 algorithm, recalls that CMA does not replace clinical assessment: investigation includes a three-generation pedigree recording pregnancy losses, stillbirths, neonatal deaths and relatives with learning difficulties or anomalies, recording malformations and anthropometry, and full dysmorphological examination [19].

5.6. Prenatal diagnosis

Prenatal CMA performed for another indication, such as advanced maternal age or ultrasound abnormalities, may detect the deletion, but the finding does not predict phenotype [1]. In a Shenzhen (China) series of 11,850 high-risk-indication amniocenteses analysed by SNP array between August 2017 and December 2024, there were 6 15q13.3 deletions (0.05%) and 9 duplications (0.08%). Three of six fetuses with deletion (50%) had non-specific ultrasound abnormalities (lateral ventriculomegaly of 10.8 and 11.2 mm, ventricular septal defect, fetal growth restriction, cleft lip and palate, malformed digits, polyhydramnios); of five tested deletions, two were maternal and three de novo, and one case was inherited from a phenotypically normal mother. Four of nine fetuses with duplication (44.4%) had ultrasound abnormalities (tricuspid regurgitation, aortic stenosis, corpus callosum dysgenesis, ventriculomegaly, enlarged gallbladder, nuchal translucency of 2.5 mm, hydronephrosis). All pregnancies with deletion were terminated, and of seven children born with duplication, one had speech and motor delay, one epilepsy at 4 years, one aortic stenosis operated on at 3 years, one strabismus and three no abnormalities at follow-up to 13 months–4.5 years [64]. The authors acknowledge the small sample, ultrasound preselection without controls and short follow-up, conclude that no specific prenatal phenotype exists and recommend postnatal neuropsychiatric surveillance even with normal ultrasound [64]. A 2026 report described apparently isolated absence of the septum pellucidum in a fetus with 15q13.3 microduplication; in the accompanying review, septo-optic dysplasia was confirmed in 21 of 112 fetuses (18.8%) with such absence [65]. The 2023 ACMG guideline recommends non-invasive prenatal screening (NIPS) for trisomies 21, 18 and 13 and sex chromosome aneuploidies, and considers detection of other microdeletions an emerging area, without a recommendation for 15q13.3 [66]. Reporting and reproductive decision-making issues are addressed in section 8.

6. Differential Diagnosis

The clinical differential is very broad because the deletion has no distinguishing features: it includes any cause of developmental delay or intellectual disability, schizophrenia, ASD and epilepsy without additional features, all chromosomal anomalies and autosomal dominant, recessive and X-linked intellectual disability genes, syndromic and non-syndromic [1]. In practice, distinction is made through genomic testing; the table compares entities most frequently considered alongside 15q13.3 deletion.

Penetrance values for comparator CNV derive from Rosenfeld and colleagues, reproduced in the Oxford reference; 15q13.3 deletion has no row in that table because it was not found in controls [19, 38].

Other neurosusceptibility CNV (15q11.2, 16p13.11, 1q21.1, 16p11.2) are the closest differential diagnoses because they share incomplete penetrance, variable expressivity and frequent inheritance from minimally affected parents; the same microarray distinguishes them, and they may coexist with 15q13.3 deletion, as in the Polish child with 1q21.1 duplication and 15q13.3 deletion [19, 50, 52]. The proximal 15q region shares LCR architecture with Prader-Willi and Angelman deletions and dup15q, but these involve the imprinted BP1/BP2–BP3 region and have recognisable phenotypes; BP3–BP5 deletion begins adjacent to BP3, near the Prader-Willi/Angelman region [1, 20]. In biallelic deletions, the combination of encephalopathy, epilepsy and visual loss requires exclusion of neuronal ceroid lipofuscinosis, and a stationary, non-progressive electronegative ERG points to TRPM1 loss [33]. In heterozygous deletion carriers with a severe phenotype, recessive OTUD7A unmasking is a differential clarified by sequencing the remaining allele [8, 48].

7. Treatments and Risk Management Strategies

7.1. Principles and absence of specific guidelines

There are no published clinical practice guidelines for 15q13.3 deletion, and searches in ClinGen, ISPG, ILAE, NSGC and ACMG databases identified no specific follow-up guideline; GeneReviews is the management reference [1, 6, 57, 58, 63]. Treatment is symptomatic and tailored to individual needs; given the high frequency of neurodevelopmental disorders, referral to a clinical psychologist for neuropsychological and developmental assessment is suggested [1]. Healthy adults with the deletion need no additional management, but their physician should be aware of increased risk of late manifestations such as schizophrenia [1].

7.2. Treatment of manifestations

Source: [1, 14].

7.3. Non-pharmacological interventions

GeneReviews describes the American model, which should be adapted to national systems. From 0 to 3 years, referral for early intervention is recommended, with occupational therapy, physiotherapy, speech and language and feeding therapy, infant mental health, specialist educators and sensory impairment specialists. From 3 to 5 years, preschool education with developmental support and an individual education plan is recommended. At all ages, the developmental paediatrician coordinates community and educational services; the education plan is reviewed annually, prioritises the least restrictive environment and inclusion in mainstream education, integrates vision and hearing consultants and necessary therapies, and in adolescence includes a transition-to-adulthood plan (in the USA, with school services until 21 years), alongside classroom adaptations such as front-row seating, assistive technology, extra time and enlarged text [1]. Children may benefit from interventions used in ASD, including applied behaviour analysis (ABA), individualised and delivered by a certified analyst; the developmental paediatrician guides behavioural management strategies and prescribing, for example ADHD drugs, and the child psychiatrist intervenes in severe aggressive or destructive behaviour [1]. For epilepsy, educating parents and caregivers about seizure presentations and coping strategies (for example Epilepsy Foundation materials) is part of treatment [1].

7.4. Pharmacological treatment: available evidence

No drug has a specific indication for 15q13.3 deletion or duplication. Available evidence is limited to small series and a case report, and none of the sources consulted states doses used in these patients; dosing follows the summary of product characteristics and epilepsy, ADHD and psychosis guidelines for each age and weight.

The α7 receptor is a pharmacological target (agonists, antagonists and positive allosteric modulators), and nicotinic agonists are approved for smoking cessation and used in other neuropsychiatric diseases; repurposing for CHRNA7 CNV would be possible but would require placebo-controlled studies [3]. In a review of 1,196 records from a mental health clinic for people with intellectual disability, 11 individuals with schizophrenia risk variants treated with antipsychotics had other CNV (six 22q11.2 deletions, two dup15q11-q13, one dup16p11.2, one dup7q11.23 and one TRIO variant), none 15q13.3, so there are no condition-specific antipsychotic data [67].

7.5. Regulatory status

In the table, FDA denotes the American Food and Drug Administration and EMA the European Medicines Agency.

Sources: [1, 53, 68]. The sources consulted did not include summaries of product characteristics for symptomatic drugs, which are consulted for each prescription.

7.6. Agents to avoid

GeneReviews suggests discouraging cannabis use because approximately 11% of carriers develop schizophrenia and cannabis is a described risk factor for this disease, although there are no deletion-specific studies. For oxcarbazepine, whether it should be avoided is unknown, given worsening in a single patient [1, 14].

7.7. Clinical trials and research

The October 2026 ClinicalTrials.gov search for “15q13.3” and “CHRNA7” found no interventional trial targeting the syndrome; CHRNA7 studies addressed schizophrenia and nicotine, CDP-choline, α7 receptor positron emission tomography or migraine, unrelated to the CNV [68]. A negative search in one registry does not prove absence of studies in other registries. There are no randomised trials, so there are no effect estimates with confidence intervals and interventions cannot be compared; response rates in retrospective series are subject to selection and publication bias, and absence of cannabidiol and ketogenic diet effects concerns three children.

7.8. Developments in the past twelve months

No authorisation applications, regulatory opinions or clinical trials of targeted therapies were identified during the period [68].

7.9. Pregnancy, perioperative care and transition

In a carrier's pregnancy, the placenta praevia signal (1.6% of pregnancies in probands) has not been confirmed with control of confounders and does not justify specific obstetric surveillance in the sources consulted [1]. In a pregnant woman with epilepsy taking antiseizure medication, general epilepsy-in-pregnancy recommendations apply, and if the child has suspected fetal anticonvulsant syndrome, microarray should investigate maternally inherited epilepsy CNV [59]. The sources consulted do not describe specific anaesthetic or perioperative risks. Transition to adulthood includes the educational transition plan and continued psychiatric surveillance because of schizophrenia risk in young adulthood [1].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

8.2. Parental studies and cascade testing

Testing a proband's parents with a method able to detect the deletion is recommended. The carrier parent may be phenotypically normal or have manifestations. If deletion is not found in either parent, it is de novo or results from parental germline or somatic and germline mosaicism; leucocyte DNA may not detect all somatic mosaicism [1]. Other relatives are at risk when a parent is a carrier [1]. GeneReviews proposes genomic testing of the proband's older and younger siblings to monitor development early [1]. Conversely, the Oxford reference notes no consensus on cascade screening for these CNV because of outcome uncertainty [19]. Decisions to test asymptomatic minors should weigh developmental surveillance benefits against future autonomy; in the case in section 10, testing of the healthy half-sister was deferred until reproductive age [34].

8.3. Prenatal diagnosis and preimplantation genetic testing

The ideal time to discuss genetic risk and reproductive options is before pregnancy, and counselling should be offered to young adult carriers or those at risk [1]. With a known familial deletion, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing (PGT) are technically possible, but the result does not predict phenotype; professionals and families differ regarding prenatal diagnosis, and most centres consider it the parents' personal decision [1]. The Oxford reference suggests that, for a de novo CNV, prenatal diagnosis may be offered for reassurance; in a carrier parent, it may be offered when the CNV is the probable cause of the child's disease, cautiously because of variable penetrance, and may not be indicated when the carrier parent has no phenotype [19]. Prenatal testing of these CNV does not accurately predict ASD development [54]. In the biallelic deletion family described in section 10, the next pregnancy was investigated by amniocentesis with SNP array, and the fetus had no 15q13.3 alteration [34]. When the carrier parent has learning difficulties, prenatal diagnostic counselling requires sufficient time and appropriate consent [19].

8.4. Unexpected prenatal findings and reporting practices

Some laboratories do not routinely report syndromes with substantially incomplete penetrance on prenatal CMA requested for ultrasound abnormalities such as increased nuchal translucency, because they are unlikely causes of the findings [19]. The new penetrance formula provides a rationale for not reporting CNV with near-zero penetrance, such as 15q13.3 duplication, in line with some prenatal reporting guidelines; deletion, with approximately 22% penetrance for intellectual disability, occupies an intermediate level [12]. The ACMG/ClinGen system permits prenatal-context-specific reporting policies if documented [60]. European prenatal reporting guidelines for neurosusceptibility loci were inaccessible in the searches performed. In the Shenzhen series, all six pregnancies with deletion were terminated, including three without ultrasound abnormalities, while seven of nine with duplication continued [64], showing the influence of counselling on decision-making.

8.5. Counselling content

Counselling should be provided by genetics professionals (clinical geneticist, genetic counsellor or specialist nurse) and explain the nature of the change, mode of transmission and implications for the proband and family [1]. It should distinguish transmission probability (50%) from manifestation probability, explain that most deletions are inherited from parents with mild or absent phenotype, that deletion does not determine severity and that penetrance estimates depend on method and phenotype considered [1, 11, 12]. Repeat counselling should be offered at reproductive age and with each new family-planning decision [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence: what each study measures

Orphanet values warrant careful interpretation. The 1–9/100 000 category with a mean of 2.5/100 000 cites Gillentine's study but does not correspond to that study's value (1/5 525, ≈18/100 000); 2.5/100 000 equals ~1/40 000, the older estimate cited by Smajlagić and Luo [2, 9, 10, 64]. Birth prevalence records (1–5/10 000 category) have values of 0.018 and 0.04 consistent with percentages (0.018% ≈ 1/5 525; 0.04% corresponds to the frequency in Norwegian parents), not rates per 100,000. Primary sources take precedence over the compilation: population deletion frequency ranges from approximately 1/10 000 to 1/2 500 according to method and population, and is tens of times higher in clinical populations with intellectual disability or IGE. D-CHRNA7–BP5 duplication is much more common (0.2% in gnomAD-SV; 1/174 to 1/186 according to Gillentine and Schaaf's review) [3, 4]. There is no significant sex difference among deletion carriers (108 men and 124 women) [3].

9.2. Regional data

In the USA, data come mainly from diagnostic laboratories (Baylor; Signature Genomics) and clinical series [3, 9, 11]. In Europe, Norway's MoBa cohort provides the only direct estimate in unselected newborns [10], Stefansson's sample includes large population data [69], UK Biobank describes effects in adult carriers [42–45], and Masurel-Paulet's French series and Pavone's Italian family document biallelic and BP3–BP5 forms [33, 49]. In Poland, in a 2013–2024 array-analysed paediatric cohort, 13 of 177 children with epilepsy-associated recurrent CNV had 15q13.3 deletion, and 4 of these had epilepsy [52]. Outside Europe and the USA, the Shenzhen prenatal series gives 0.05% deletions and 0.08% duplications among high-risk amniocenteses [64].

The preprint by Höps and colleagues suggests that the structural haplotype predisposing to BP4–BP5 CNV is much more frequent in Europeans (68.4%) than East Asians (5.1%), potentially stratifying new rearrangement risk more than tenfold [31]; Goh and colleagues acknowledge that ancestry and geographical differences between affected cohorts and controls may explain some of the duplication excess in clinical cohorts [12]. These data have not been confirmed in peer-reviewed population studies.

In Brazil, a public reference centre described a 12-year-old boy with ASD and intellectual disability, normal karyotype and FMR1 and a 418 kb duplication at 15q13.3 (31,732,520–32,151,362 ×3, including OTUD7A and CHRNA7), classified by the laboratory as of uncertain significance, with speech apraxia, macrocephaly, echolalia, food selectivity and self-injury [70]; an observational study from a Brazilian clinical genetics service lists one individual with 7q11.22 deletion and 15q13.3 duplication associated with autism [71]. The sources consulted include no Portuguese data; this absence does not demonstrate absence of published data.

9.3. Special populations

Asymptomatic adults identified through cascade testing or incidental findings need no additional management but benefit from information on schizophrenia risk [1]. Carrier women with epilepsy who become pregnant should be considered in the context of fetal anticonvulsant syndrome [59]. Carrier parents with learning difficulties need adapted counselling [19].

9.4. Reference networks and patient associations

The relevant European reference network is ERN ITHACA, dedicated to rare congenital malformations and rare intellectual disability [15]. The British association Unique publishes family guides on 15q13.3 microdeletion (also in French, German and an easy-read version) and 15q13.3 microduplications, with a Portuguese version [16]. Chromosome Disorder Outreach (USA) supports families with chromosomal changes [17]. The Simons Searchlight registry (NCT01238250) collects natural history data from families with the deletion and provides a family guide [18]. DECIPHER supports professional CNV interpretation [19]. The sources consulted identified no patient association exclusive to 15q13.3.

10. Illustrative Clinical Case

Simon and colleagues described in 2019 a girl with homozygous 15q13.3 deletion [34]. She was the second pregnancy of a 24-year-old mother and a 21-year-old father with ADHD; the 5-year-old maternal half-sister was healthy, and there was no known consanguinity. Pregnancy was uneventful until approximately 36 weeks, when ultrasound showed slower head growth; birth was vaginal, induced at 41 weeks, with weight approximately 3.0 kg and length approximately 52 cm. The child was assessed in neurology for hypotonia and developmental delay. She had long eyelashes, epicanthic folds and slightly anteverted nostrils, without significant dysmorphism (article figure 1, facial photograph: https://pmc.ncbi.nlm.nih.gov/articles/PMC6935653/figure/ccr32403-fig-0001/). She did not fix or track objects or faces, had conjugate but roving eye movements with intermittent upward deviation and brief horizontal pendular nystagmoid intrusions in the first months, marked diffuse hypotonia, reduced muscle bulk, absent biceps reflexes and quadriceps reflexes graded 1 out of 4. Ophthalmological assessment at 5 months showed optic nerve hypoplasia and delayed visual maturation.

Brain MRI at 4 months showed normal structure and volume, with slightly delayed myelination for age. EEG showed almost continuous high-amplitude occipital slowing (2–4 Hz awake and 1–3 Hz asleep) and intermittent focal spikes, right occipital at 7 months and bilateral paracentral at 11 months, without clinical seizures up to 11 months. Electrocardiogram and echocardiogram were normal, and MRI showed an aberrant right subclavian artery. SNP array (Illumina, more than 845,000 markers) revealed a homozygous 2.0 Mb loss at 15q13.2q13.3 (hg19 chr15:30938341-32926776), including FAN1, MTMR10, MIR211, TRPM1, KLF13, OTUD7A, CHRNA7 and ARHGAP11A, among others, and a paternal 122 kb gain at 9q34.3 (partial COL5A1) considered likely benign. Both parents had the same deletion heterozygously. In the next pregnancy, amniocentesis with SNP array showed a fetus without a 15q13.3 alteration, and half-sister testing was deferred until reproductive age [34].

The authors compared the case with 11 published patients and attributed retinal and ophthalmological findings to TRPM1 loss, acknowledging a cortical contribution from CHRNA7 [34]. The case illustrates three clinical points: biallelic deletion produces a severe consistent phenotype, distinct from heterozygous variability; two parents with heterozygous deletion and mild or absent phenotype may have a severely affected child, with 25% risk in each pregnancy; and diagnosis enabled targeted prenatal diagnosis. The management described follows general GeneReviews assessment recommendations (neurology, EEG, ophthalmology, cardiology, genetic counselling) [1].

11. Prognosis and Long-term Follow-up

11.1. Prognosis

The individual prognosis of a heterozygous carrier is unpredictable, ranging from normal development to substantial impairment; cognitive impairment, when present, is generally mild [1]. Hypotonia improves during childhood, and independent walking is acquired at a mean of 21.5 months [1]. Epilepsy, predominantly absence epilepsy, responds to valproate in some children, but one-third are drug-resistant [14]. Schizophrenia risk persists in adulthood (approximately 11% of ascertained adults; estimated population penetrance 4.7%) [1, 11]. In adult general population carriers without a neurodevelopmental diagnosis, UK Biobank studies describe modest cognitive deficits and greater medical morbidity for neurodevelopmental CNV collectively [43, 44]. The sources consulted provide no survival data for the heterozygous form. In biallelic deletions, disease is severe from the neonatal period, with frequently refractory epilepsy and visual impairment, and one published patient died at 13 years [34]. D-CHRNA7–BP5 duplication has minimal population effects [4, 43].

11.2. Assessment after diagnosis

Source: [1, 33, 34].

11.3. Surveillance

The intervals given correspond to GeneReviews recommendations, which specify no fixed intervals in years for examinations other than annual audiology in childhood [1].

12. Summary and Final Considerations

15q13.3 recurrent deletion is a copy number change of approximately 1.5–2.0 Mb between BP4 and BP5, formed through non-allelic homologous recombination between segmental duplications, removing FAN1, MTMR10, TRPM1, KLF13, OTUD7A and CHRNA7. It is one of the most frequent neurosusceptibility CNV: occurring in approximately 1/5 525 to 1/2 500 births, approximately 0.3% of people with intellectual disability and approximately 1% of people with idiopathic generalised epilepsy. It has no recognisable phenotype; in ascertainment-adjusted series, approximately 59% of identified carriers have developmental delay or intellectual disability, approximately 30% epilepsy, predominantly childhood-onset absences, and approximately 11% of adults schizophrenia, but population penetrance is much lower, approximately 22% for intellectual disability when background risk is excluded. Most deletions are inherited, often from a parent with mild or absent phenotype, making counselling focus on distinguishing transmission probability (50%) from manifestation probability.

OTUD7A and CHRNA7 are candidate genes for neuropsychiatric manifestations; animal models and human neurones point to OTUD7A as a major contributor, and its biallelic loss causes a recessive disorder with hypotonia and seizures, potentially resulting from a 15q13.3 deletion in trans with a sequence variant. Biallelic deletions produce severe encephalopathy with cortical and retinal visual impairment, the latter related to TRPM1. BP4–BP5 microduplication has very low penetrance, and D-CHRNA7–BP5 duplication, common in the population, is now generally considered likely benign.

Diagnosis rests on microarray or genomic sequencing with CNV analysis, followed by parental studies. There is no specific treatment or dedicated guideline; management is symptomatic and multidisciplinary, with early intervention, educational support, epilepsy treatment attentive to possible worsening with sodium channel blockers, prolonged psychiatric surveillance and genetic counselling before pregnancy. New penetrance estimates and the 2026 ClinGen reassessment reinforce the need to communicate risk using phenotype- and method-specific figures.

13. References

1. van Bon BWM, Mefford HC, de Vries BBA, Schaaf CP. 15q13.3 Recurrent Deletion. 2010 Dec 23 [updated 2022 Nov 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK50780/. PMID: 21290787.
2. Orphanet. 15q13.3 microdeletion syndrome (ORPHA:199318) [Internet]. Paris: INSERM; epidemiological and age-of-onset data (Orphadata) [cited 2026 Oct 9]. Available from: https://www.orpha.net/en/disease/detail/199318
3. Gillentine MA, Schaaf CP. The human clinical phenotypes of altered CHRNA7 copy number. Biochem Pharmacol. 2015;97(4):352-362. doi:10.1016/j.bcp.2015.06.012. PMID: 26095975. PMC4600432.
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