Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss

abstract: ...Background The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a casecontrol cohort. Results Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B , for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6 , OTOA , and STRC , encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR=3.91, 95% CI: 1.62-9.40, p=1.4510 -7 ). Conclusions We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1155) contains supplementary material, which is available to authorized users.

... hearing (e.g. GJB6 , OTOA , and STRC , encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR=3.91, 95% CI: 1.62-9.40, p=1.4510 -7 ). Conclusions We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the

... four and five individuals, respectively) and 13 unrelated probands. Finally, we conducted the first high-resolution, genome-wide CNV investigation for hearing loss. We report several novel CNV associations found in a cohort of 150 affected individuals and 157 controls, including a deletion on chromosome 16 encompassing the PDXDC1 gene, the has-mir-1972 micro RNA, and part of the NPIP . These results support our hypothesis that SNHL may manifest due to either underlying shared or individually rare

... Number 6 (Biodiscovery) and NimbleScan 2.6 (NimbleGen). Association testing was performed for genomic regions affected by CNVs including single loci, genes, and pathways, as well as for overall CNV load. We found an associated deletion on chromosome 16 encompassing the PDXDC1 gene (OR=3.91, 95% CI: 1.62-9.40, p=1.45 10 -7 ) as well as other less significant CNV associations. Additionally, we performed SNP genotyping of 150 cases and 28 controls using the Illumina 1M SNP array and carried out a

... : Figure S2). CNVs were tested for association with the phenotype using the Classic calculation option of the Comparisons function in Nexus 6.0. Smallest regions of overlap of the individual CNVs were used. The most significant association is an approximately 72.5kb (smallest region of overlap) deletion on chromosome 16 (hg18; chr16:14,956,245-15,028,783) encompassing the first 15 exons of the PDXDC1 gene, the has-mir-1972 micro RNA, and the intergenic region between PDXDC1 and the upstream NPIP gene

... algorithms called the CNV (Figure 5 b). Figure 5 Chromosome 16p13.11 deletion associated with SNHL. a . The frequencies of the deletion on chromosome 16 encompassing part of the PDXDC1 gene are indicated for the entire sample set, as well as separated out for the affected individuals and controls (highlighted in the black box). Green shading indicates duplications whereas red shading indicates deletions. The horizontal tracks indicate the coordinates of the position along chromosome 16p13.11 (hg18

... from both CNV calling algorithms were the most functionally promising (Table 4 ). As expected, the three genes in the deletion on chromosome 16 ( NOMO1 , NPIP and PDXDC1) found to be associated were among the top candidates in this second set of association tests. Additionally, the OTOA gene, known to be associated with SNHL [ 1 ], was found to be significantly associated in this cohort. The NBPF4 gene was found to be associated as well. This gene has no known function, but it is one of five genes that lies within the region of overlap of two previously discovered deafness associated genomic regions, DFNB82 and DFNB32 [ 15 ]. Table 4 Interesting genes significantly associated with SNHL Gene Nexus NimbleScan Case frequency Control frequency OR 95% CI FET p-value Case frequency Control frequency OR 95% CI FET p-value NOMO1 41 13 4.20 9 4 2.46 2.14-8.21 0.74-8.16 1.88E-05 1.63E-01 GRAPL 68 38 2.62 43 27 1.95 1.61-4.26 1.13-3.36 1.26E-04 2.09E-02 PDXDC1 41 16 3.33 24 9 3.15 1.78-6.26

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Gene: PDXDC1 - pyridoxal-dependent decarboxylase domain containing 1 - (NCBI)

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