Whole-Exome Sequencing to Decipher the Genetic Heterogeneity of Hearing Loss in a Chinese Family with Deaf by Deaf Mating

Abstract

Inherited deafness has been shown to have high genetic heterogeneity. For many decades, linkage analysis and candidate gene approaches have been the main tools to elucidate the genetics of hearing loss. However, this associated study design is costly, time-consuming, and unsuitable for small families. This is mainly due to the inadequate numbers of available affected individuals, locus heterogeneity, and assortative mating. Exome sequencing has now become technically feasible and a cost-effective method for detection of disease variants underlying Mendelian disorders due to the recent advances in next-generation sequencing (NGS) technologies. In the present study, we have combined both the Deafness Gene Mutation Detection Array and exome sequencing to identify deafness causative variants in a large Chinese composite family with deaf by deaf mating. The simultaneous screening of the 9 common deafness mutations using the allele-specific PCR based universal array, resulted in the identification of the 1555A>G in the mitochondrial DNA (mtDNA) 12S rRNA in affected individuals in one branch of the family. We then subjected the mutation-negative cases to exome sequencing and identified novel causative variants in the MYH14 and WFS1 genes. This report confirms the effective use of a NGS technique to detect pathogenic mutations in affected individuals who were not candidates for classical genetic studies.

Comorbidity in the Tunisian population

“…Moreover, they have opportunity to meet in hospitals, patient supporting groups or specialized schools. This could explain association of distinct genetic diseases of the same/different group but also the cases of compound heterozygotes (12). Comorbidity due to homogamy, although not yet reported in the Tunisian population, has to be kept in mind.…”

Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss

“…Two of the case reports used comprehensive genetic testing for diagnosis of families with and found both non-syndromic and syndromic forms of hearing loss segregating simultaneously 22,23 . Two studies identified families with three forms of hearing loss segregating simultaneously 23,24 . And one study identified a possibly life threatening disorder, Long QT syndrome caused by a mutation in KCNQ1 , with exome sequencing, in a patient with what appeared to be non-syndromic hearing loss 25 .…”

Targeted Next-Generation Sequencing for Clinical Diagnosis of 561 Mendelian Diseases

“…The primary advantage of NGS over Sanger method is the inexpensive production of large amounts of sequencing data [ 3 ]. With unprecedented high throughput, highly parallel and base-pair resolution data of NGS, whole-exome sequencing (WES) and whole-genome sequencing (WGS) are all applied in the diagnostic testing or carrier screening of Mendelian genetic disorders [ 4 – 7 ]. WGS and WES yield myriad of genetic variations which have an advantage in carrier screening.…”