Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes

• DOI: 10.1186/s12920-018-0395-1
• Publication Date: 2018-09-04T12:42:30Z
• Authors: Morag A. Lewis; Lisa S. Nolan; Barbara A. Cadge; Lois J. Matthews; Bradley A. Schulte; Judy R. Dubno; Karen P. Steel; Sally J. Dawson
• Keywords: Sanger sequencing; Exome; Candidate gene

Deafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive loss. Despite several genome-wide association studies adult status, it remains unclear whether genetic architecture this sensory loss consists multiple rare variants each large effect size or susceptibility small medium effects. As next generation sequencing now being utilised clinical diagnosis, our aim was explore viability diagnosing cause using whole exome individual subjects as setting. We performed thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts 1479 people Every carried predicted pathogenic at least ten deafness-associated genes; similar findings were obtained an analysis 1000 Genomes Project data unselected status. have identified putative causal deafness and novel candidate genes, including NEDD4 NEFH that mutated individuals. The high frequency predicted-pathogenic detected unexpected has significant implications current diagnostic deafness. Our suggest clinic setting, efforts should be made a) confirm key sequence results by Sanger sequencing, b) assess segregations phenotypes within family if all possible, c) use caution applying pathogenicity prediction algorithms purposes. conclude there may number affecting ageing population, genes. frequent both hearing-impaired sample larger auditory function suggests reference population interpreting very good their age rather than population.