Abstract
BackgroundThe genetic heterogeneity of sensorineural hearing loss is a major hurdle to the efficient discovery of disease-causing genes. We designed a multiphasic analysis of copy number variation (CNV), linkage, and single nucleotide variation (SNV) of whole exome sequencing (WES) data for the efficient discovery of mutations causing nonsyndromic hearing loss (NSHL).ResultsFrom WES data, we identified five distinct CNV loci from a NSHL family, but they were not co-segregated among patients. Linkage analysis based on SNVs identified six candidate loci (logarithm of odds [LOD] >1.5). We selected 15 SNVs that co-segregated with NSHL in the family, which were located in six linkage candidate loci. Finally, the novel variant p.M305T in ACTG1 (DFNA20/26) was selected as a disease-causing variant.ConclusionsHere, we present a multiphasic CNV, linkage, and SNV analysis of WES data for the identification of a candidate mutation causing NSHL. Our stepwise, multiphasic approach enabled us to expedite the discovery of disease-causing variants from a large number of patient variants.
Highlights
The genetic heterogeneity of sensorineural hearing loss is a major hurdle to the efficient discovery of disease-causing genes
A two-step approach of linkage analysis using single nucleotide polymorphism (SNP) microarrays to detect high logarithm of odds (LOD) score regions and subsequent targeted re-sequencing of regions of interest has been utilized in many genomic studies to intensify the power of detection [7]
Clinical features of a nonsyndromic hearing loss (NSHL) family We identified a Korean family with six members affected by NSHL and seven unaffected members (Figure 1A)
Summary
The genetic heterogeneity of sensorineural hearing loss is a major hurdle to the efficient discovery of disease-causing genes. We designed a multiphasic analysis of copy number variation (CNV), linkage, and single nucleotide variation (SNV) of whole exome sequencing (WES) data for the efficient discovery of mutations causing nonsyndromic hearing loss (NSHL). Exome sequencing provides a powerful method with which to identify disease-causing single nucleotide variations (SNVs) in Mendelian disorders [1,2,3,4]. Genetic linkage analysis has been a powerful tool for isolating potential causal candidate variants. A two-step approach of linkage analysis using single nucleotide polymorphism (SNP) microarrays to detect high logarithm of odds (LOD) score regions and subsequent targeted re-sequencing of regions of interest has been utilized in many genomic studies to intensify the power of detection [7]. There are many efforts to use coding SNP information from WES data to facilitate genetic linkage mapping
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