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

PLoS One. 2014 May 9;9(5):e97040. doi: 10.1371/journal.pone.0097040. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Deafness / genetics
  • Exome / genetics
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / physiology
  • Female
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / physiology
  • Genes, Dominant / genetics*
  • Genotype
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Molecular Sequence Data
  • Pedigree
  • Phenotype*
  • Republic of Korea
  • Sequence Analysis, DNA

Substances

  • Extracellular Matrix Proteins
  • GPI-Linked Proteins
  • Membrane Glycoproteins
  • TECTA protein, human
  • nidogen

Supplementary concepts

  • Nonsyndromic Deafness

Grants and funding

This study was supported by the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (Nos. A080588 and A111377), and the National Research Foundation of Korea grant funded by the Korean government (Ministry of Education, Science, and Technology; No. 20120009215). The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.