Copy number variants are a common cause of non-syndromic hearing loss

Genome Medicine (Impact Factor: 5.34). 05/2014; 6(5):37. DOI: 10.1186/gm554
Source: PubMed


Copy 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.

We 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.

Of 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).

CNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.

15 Reads
  • Source
    • "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, 2012; Asadollahi et al., 2014; Bademci et al., 2014; Shearer et al., 2014]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37372 · 2.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Copy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. Many CNVs have been associated with either resistance to diseases or identified as the cause of diseases. Currently little is known about the role of CNVs in causing deafness. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. Here we detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing. Methods Coding regions of the deafness genes were captured by a hybridization-based method and processed through the standard next-generation sequencing (NGS) protocol using the Illumina platform. Samples hybridized together in the same reaction were analyzed to obtain CNVs. A read depth based method was used to measure CNVs at the resolution of a single exon. Results were validated by the quantitative PCR (qPCR) based method. Results Among 79 sporadic cases clinically diagnosed with sensorineural hearing loss, we identified previously-reported disease-causing sequence mutations in 16 cases. In addition, we identified a total of 97 CNVs (72 CNV gains and 25 CNV losses) in 27 deafness genes. The CNVs included homozygous deletions which may directly give rise to deleterious effects on protein functions known to be essential for hearing, as well as heterozygous deletions and CNV gains compounded with sequence mutations in deafness genes that could potentially harm gene functions. Conclusions We studied how CNVs in known deafness genes may result in deafness. Data provided here served as a basis to explain how CNVs disrupt normal functions of deafness genes. These results may significantly expand our understanding about how various types of genetic mutations cause deafness in humans.
    BMC Ear Nose and Throat Disorders 09/2014; 14(1):9. DOI:10.1186/1472-6815-14-9
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.
    The American Journal of Human Genetics 09/2014; 95(4). DOI:10.1016/j.ajhg.2014.09.001 · 10.93 Impact Factor

Full-text (5 Sources)

15 Reads
Available from
Jul 21, 2015