Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes

Abstract Background Heterogeneous genetic loci contribute to hereditary hearing loss; more than 100 deafness genes have been identified, and the number is increasing. To detect pathogenic variants in multiple deafness genes, in addition to novel candidate genes associated with hearing loss, whole exome sequencing (WES), followed by analysis prioritizing genes categorized in four tiers, were applied. Results Trios from families with non-syndromic or syndromic hearing loss (n = 72) were subjected to WES. After segregation analysis and interpretation according to American College of Medical Genetics and Genomics guidelines, candidate pathogenic variants in 11 previously reported deafness genes ( STRC , MYO15A , CDH23 , PDZD7 , PTPN11 , SOX10 , EYA1 , MYO6 , OTOF , OTOG , and ZNF335 ) were identified in 21 families. Discrepancy between pedigree inheritance and genetic inheritance was present in one family. In addition, eight genes ( SLC12A2 , BAIAP2L2 , HKDC1 , SVEP1 , CACNG1 , GTPBP4 , PCNX2 , and TBC1D8 ) were screened as single candidate genes in 10 families. Conclusions Our findings demonstrate that four-tier assessment of WES data is efficient and can detect novel candidate genes associated with hearing loss, in addition to pathogenic variants of known deafness genes.