Bi-allelic Pro291Leu variant in KCNQ4 leads to early onset non-syndromic hearing loss

Gene. 2019 Jul 15;705:109-112. doi: 10.1016/j.gene.2019.04.064. Epub 2019 Apr 24.

Abstract

Variants of KCNQ4 are one of the most common causes of dominantly inherited nonsyndromic hearing loss. We investigated a consanguineous family in which two individuals had prelignual hearing loss, apparently inherited in a recessive mode. Whole-exome sequencing analyses demonstrated genetic heterogeneity as variants in two different genes segregated with the phenotype in two branches of the family. Members in one branch were homozygous for a pathogenic variant of TMC1. The other two affected individuals were homozygous for a missense pathogenic variant in KCNQ4 c.872C>T; p.(Pro291Leu). These two individuals had prelingual, progressive moderate to severe hearing loss, while a heterozygous carrier had late onset mild hearing loss. Our work demonstrates that p.Pro291L variant is semi-dominantly inherited. This is the first report of semi-dominance of a KCNQ4 variant.

Keywords: ADNSHL; ARNSHL; BHCMG; Baylor-Hopkins Center for Mendelian Genomics; DFNA2A; Deafness; Hearing loss; KCNQ4; Pakistan; WES; Whole exome sequencing.

MeSH terms

  • Age of Onset
  • Consanguinity
  • Deafness / genetics*
  • Female
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Humans
  • KCNQ Potassium Channels / genetics*
  • Leucine / genetics
  • Male
  • Mutation, Missense*
  • Pedigree
  • Proline / genetics
  • Whole Exome Sequencing / methods*

Substances

  • KCNQ Potassium Channels
  • KCNQ4 protein, human
  • Proline
  • Leucine

Supplementary concepts

  • Nonsyndromic Deafness