Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA.

Abstract

Postlingual progressive hearing loss, affecting primarily the high frequencies,

is the clinical finding in most cases of autosomal dominant nonsyndromic hearing

loss (ADNSHL). The molecular genetic etiology of ADNSHL is extremely

heterogeneous. We applied whole-exome sequencing to reveal the genetic etiology

of high-frequency hearing loss in a mid-sized Korean family without any prior

linkage data. Whole-exome sequencing of four family members (two affected and two

unaffected), together with our filtering strategy based on comprehensive

bioinformatics analyses, identified 21 potential pathogenic candidates. Sanger

validation of an additional five family members excluded 20 variants, leaving

only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate.

This variant resides in the entactin (ENT) domain and co-segregated perfectly

with non-progressive high-frequency hearing loss in the family. It was absent

among 700 ethnically matched control chromosomes, and the T237 residue is

conserved among species, which supports its pathogenicity. Interestingly, this

finding contrasted with a previously proposed genotype-phenotype correlation in

which variants of the ENT domain of TECTA were associated with mid-frequency

hearing loss. Based upon what we observed, we propose a novel "genotype to

phenotype" correlation in the ENT domain of TECTA. Our results shed light on

another important application of whole-exome sequencing: the establishment of a

novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant

hearing loss.