Dataset Information

Clinical Implications of Chromosome 16 Copy Number Variation.

ABSTRACT: Chromosome 16 is one of the gene-rich chromosomes; however, approximately 10% of the chromosome 16 sequence is composed of segmental copies, which renders this chromosome instable and predisposes it to rearrangements via frequent nonallelic homologous recombination. Microarray technologies have enabled the analysis of copy number variations (CNV), which may be associated with the risk of developing complex diseases. Through comparative genomic hybridisation in 1,298 patients, we detected 18 cases with chromosome 16 CNV. We identified 2recurrent CNV regions, including 1 at 16p13.11 in 4 patients and another at 16p11.2 in 7 patients. We also detected atypical chromosome 16 rearrangements in 7 patients. Furthermore, we noted an increased frequency of co-occurring genomic changes, supporting the two-hit hypothesis to explain the phenotypic variability in the clinical presentation of CNV syndromes. Our findings can contribute to the creation of a chromosome 16 disease map based on regions that may be associated with disease development.

SUBMITTER: Atli EI

PROVIDER: S-EPMC9149555 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Clinical Implications of Chromosome 16 Copy Number Variation.

Atli Emine Ikbal EI Yalcintepe Sinem S Atli Engin E Demir Selma S Mail Cisem C Gurkan Hakan H

Molecular syndromology 20211215 3

Chromosome 16 is one of the gene-rich chromosomes; however, approximately 10% of the chromosome 16 sequence is composed of segmental copies, which renders this chromosome instable and predisposes it to rearrangements via frequent nonallelic homologous recombination. Microarray technologies have enabled the analysis of copy number variations (CNV), which may be associated with the risk of developing complex diseases. Through comparative genomic hybridisation in 1,298 patients, we detected 18 case ...[more]

PMID: 35707588

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Project description:ObjectiveCopy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available.MethodsWe assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy.ResultsOf 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs.SignificanceThe use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Dataset Information

Clinical Implications of Chromosome 16 Copy Number Variation.

Publications

Clinical Implications of Chromosome 16 Copy Number Variation.

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