Identification of Copy Number Variants Through Whole-Exome Sequencing in Autosomal Recessive Nonsyndromic Hearing Loss

Bademci, Güney; Diaz‐Horta, Oscar; Guo, Shengru; Duman, Duygu; Booven, Derek Van; Foster, Joseph; Cengiz, Filiz Başak; Blanton, Susan H.; Tekin, Mustafa

doi:10.1089/gtmb.2014.0121

Cited by 30 publications

(20 citation statements)

References 15 publications

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“…[28][29][30][31][32][33][34] A relatively high frequency of STRC deletions was found in our Dutch population (2%), as has also been reported in other populations. 8,9 In one case (ISO31), we found causative variants in a gene that is associated with an identifiable phenotype and segregating with a recessive inheritance pattern.…”

Section: Discussionsupporting

confidence: 89%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

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Section: Discussionsupporting

confidence: 89%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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“…An earlier study from our group in patients with syndromic hearing loss revealed that chromosomal imbalances are a common cause of the phenotypes . In recent years, some publications have reported that rare copy number alterations are also a cause of non‐syndromic hearing loss . As anticipated, CNVs detected in non‐syndromic patient cohorts were small and harboured one or a small number of genes.…”

Section: Discussionsupporting

confidence: 66%

Genomic copy number alterations in non‐syndromic hearing loss

et al. 2015

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Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment.

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“…Role of copy number variants (CNVs) in human genetic disorders are well‐recognized. Copy number variation plays major role particularly in the genetic etiology of many developmental disorders including autism, intellectual disability (ID) and hearing loss [Marshall and Scherer, ; Asadollahi et al, ; Bademci et al, ; Shearer et al, ].…”

Section: Introductionmentioning

confidence: 99%

Xq21.31–q21.32 duplication underlies intellectual disability in a large family with five affected males

Basit

Malibari

Albalawi

et al. 2015

American J of Med Genetics Pt A

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X-linked intellectual disability is the most common form of neurological disorder in male and accounts for 5-10% of incidence in the population. Copy number variants (CNVs) have been studied extensively to identify genomic regions responsible for neurological disorders. Array CGH and SNP genotyping have identified several CNVs on X-chromosome in patients with X-linked intellectual disability. We genotyped 2.5 million SNPs in 10 individuals of a 4 generation family segregating X-linked intellectual disability using Illumina Infinium BeadChip assay. Whole genome genotyping data analysis identified a single duplication of 3.95 Mb on X-chromosome in all five affected male individuals. This CNV is inherited from a healthy mother. All five affected individuals manifest moderate to severe intellectual disability, seizures and behavioral abnormalities. X-chromosome inactivation analysis showed that X-chromosome of the mother with duplication is completely inactivated which has also been found in daughters.

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Identification of Copy Number Variants Through Whole-Exome Sequencing in Autosomal Recessive Nonsyndromic Hearing Loss

Cited by 30 publications

References 15 publications

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Genomic copy number alterations in non‐syndromic hearing loss

Xq21.31–q21.32 duplication underlies intellectual disability in a large family with five affected males

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