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The importance of phase analysis in multiexon copy number variation detected by aCGH in autosomal recessive disorder loci.

ABSTRACT: Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to the exonic level, however it has its limitations. It cannot detect balanced structural variation nor determine the phase of copy number variants. Heterozygous multi-exonic copy number variation in autosomal recessive genes should be interpreted in the context of a clinical phenotype, and, if warranted, phase analysis should be performed before sequence analysis for that gene is pursued. This patient emphasizes the need of obtaining clinical information and determining the phase in multi-exonic copy number variants for accurate diagnosis and risk counseling.

SUBMITTER: Gillentine MA

PROVIDER: S-EPMC6240332 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The importance of phase analysis in multiexon copy number variation detected by aCGH in autosomal recessive disorder loci.

Gillentine Madelyn A MA Schaaf Christian P CP Patel Ankita A

American journal of medical genetics. Part A 20170620 9

Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to t ...[more]

PMID: 28631888

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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 importance of phase analysis in multiexon copy number variation detected by aCGH in autosomal recessive disorder loci.

Publications

The importance of phase analysis in multiexon copy number variation detected by aCGH in autosomal recessive disorder loci.

Similar Datasets

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