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The clinical significance of small copy number variants in neurodevelopmental disorders.

ABSTRACT: Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500?kb has not been well elucidated in a clinical context.By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500?kb in a cohort of 714 patients with undiagnosed NDDs.We detected 96 rare CNVs <500?kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130?kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear.These results verify the diagnostic relevance of genome-wide rare CNVs <500?kb, which were found pathogenic in ?2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions.

SUBMITTER: Asadollahi R

PROVIDER: S-EPMC4173859 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The clinical significance of small copy number variants in neurodevelopmental disorders.

Asadollahi Reza R Oneda Beatrice B Joset Pascal P Azzarello-Burri Silvia S Bartholdi Deborah D Steindl Katharina K Vincent Marie M Cobilanschi Joana J Sticht Heinrich H Baldinger Rosa R Reissmann Regina R Sudholt Irene I Thiel Christian T CT Ekici Arif B AB Reis André A Bijlsma Emilia K EK Andrieux Joris J Dieux Anne A FitzPatrick David D Ritter Susanne S Baumer Alessandra A Latal Beatrice B Plecko Barbara B Jenni Oskar G OG Rauch Anita A

Journal of medical genetics 20140808 10

<h4>Background</h4>Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context.<h4>Methods</h4>By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs.<h4>Results</h4>We detected 96 r ...[more]

PMID: 25106414

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Project description:Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR?=?2.59; p?=?0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR?=?5.62; p?=?0.0002), but not in females (OR?=?1.19, p?=?0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR?=?2.59; p?=?0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Dataset Information

The clinical significance of small copy number variants in neurodevelopmental disorders.

Publications

The clinical significance of small copy number variants in neurodevelopmental disorders.

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