Utilization of Exome Sequencing for Diagnosis and Discovery of Genetic Causes of Sensorineural Hearing Loss

Objectives: Exome sequencing (ES) is a single platform test that screens the exons of nearly all genes and is increasingly being used in the clinical diagnosis of hearing loss due to the large number of genes etiologically implicated. Our goals were to explore (1) the utility and limitations of ES for diagnosis in children with sensorineural hearing loss (SNHL) and (2) its ability to discover novel genes causing SNHL. Methods: Thirty‐six children with bilateral SNHL underwent ES: 26 without an etiology for their SNHL after standard clinical testing, and a control group of 10 with known mutations. Exome variants were initially filtered using a list of 264 genes associated with hearing loss. Results: In the 10 children with known mutations, all were correctly identified by ES except 3 large deletions. Analysis of the 26 unknown samples found likely pathogenic mutations in 8 (31%). A definitive diagnosis was obtained in 1 additional child, who had an unusual MITF mutation that led to the diagnosis of Waardenburg syndrome. In one other family, a novel candidate gene was identified which previously has never been implicated in human disease. Affected children in that family had profound SNHL accompanied by malformation of the vestibular labyrinth. Mutations in this gene segregated as expected among the 8 family members. Conclusions: ES is a powerful tool for both diagnosis and discovery for genetically heterogeneous conditions like SNHL. Despite limitations inherent to using gene lists and only sequencing exons, this technology has great promise for helping ascertain the etiology of SNHL in children.