Abstract
BackgroundCopy number variants (CNVs) are a well-recognized cause of genetic disease; however, methods for their identification are often gene-specific, excluded as ‘routine’ in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. We aimed to incorporate a method for CNV identification as part of our standard analysis pipeline and to determine the contribution of CNVs to genetic hearing loss.MethodsWe used targeted genomic enrichment and massively parallel sequencing to isolate and sequence all exons of all genes known to cause NSHL. We completed testing on 686 patients with hearing loss with no exclusions based on type of hearing loss or any other clinical features. For analysis we used an integrated method for detection of single nucleotide changes, indels and CNVs. CNVs were identified using a previously published method that utilizes median read-depth ratios and a sliding-window approach.ResultsOf 686 patients tested, 15.2% (104) carried at least one CNV within a known deafness gene. Of the 38.9% (267) of individuals for whom we were able to determine a genetic cause of hearing loss, a CNV was implicated in 18.7% (50). We identified CNVs in 16 different genes including 7 genes for which no CNVs have been previously reported. CNVs of STRC were most common (73% of CNVs identified) followed by CNVs of OTOA (13% of CNVs identified).ConclusionCNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.
Highlights
Copy number variants (CNVs) are a well-recognized cause of genetic disease; methods for their identification are often gene-specific, excluded as ‘routine’ in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines
Copy number variants identified We identified 143 CNVs in 16 genes in 686 patients with hearing loss (Table 2; Additional file 2)
We identified a probable genetic cause of hearing loss, be it a single nucleotide variant, indel, or CNV, in 38.9% of patients enrolled in this study (267/686)
Summary
Copy number variants (CNVs) are a well-recognized cause of genetic disease; methods for their identification are often gene-specific, excluded as ‘routine’ in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. The Human Gene Mutation Database contains 148,413 reported disease-causing mutations in 6,137 genes [3] (accessed February 2014) Of these mutations, 89.6% are single nucleotide changes and small (< 20 bp) indels. Examples of the contribution of CNVs to human genetic disease include Charcot-Marie-Tooth neuropathy 1A (autosomal dominant), Gaucher disease (autosomal recessive), hemophilia A (X-linked) and mental retardation (complex genetics) (reviewed in [4])
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