Novel Mutations in CLPP, LARS2, CDH23, and COL4A5 Identified in Familial Cases of Prelingual Hearing Loss

Genes (Basel). 2020 Aug 22;11(9):978. doi: 10.3390/genes11090978.

Abstract

We report the underlying genetic causes of prelingual hearing loss (HL) segregating in eight large consanguineous families, ascertained from the Punjab province of Pakistan. Exome sequencing followed by segregation analysis revealed seven potentially pathogenic variants, including four novel alleles c.257G>A, c.6083A>C, c.89A>G, and c.1249A>G of CLPP, CDH23, COL4A5, and LARS2, respectively. We also identified three previously reported HL-causing variants (c.4528C>T, c.35delG, and c.1219T>C) of MYO15A, GJB2, and TMPRSS3 segregating in four families. All identified variants were either absent or had very low frequencies in the control databases. Our in silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MYO15A, GJB2, TMPRSS3, and CDH23 were classified as "pathogenic" or "likely pathogenic", while the variants in CLPP and LARS2 fall in the category of "uncertain significance" based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. This paper highlights the genetic diversity of hearing disorders in the Pakistani population and reports the identification of four novel mutations in four HL families.

Keywords: Pakistan; genetic heterogeneity; genetic testing; prelingual hearing loss; whole-exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acyl-tRNA Synthetases / genetics*
  • Cadherin Related Proteins
  • Cadherins / genetics*
  • Child
  • Child, Preschool
  • Collagen Type IV / genetics*
  • Deafness / epidemiology
  • Deafness / genetics*
  • Deafness / pathology
  • Endopeptidase Clp / genetics*
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Humans
  • Male
  • Mutation*
  • Pakistan / epidemiology
  • Pedigree
  • Prognosis
  • Young Adult

Substances

  • CDH23 protein, human
  • COL4A5 protein, human
  • Cadherin Related Proteins
  • Cadherins
  • Collagen Type IV
  • ClpP protein, human
  • Endopeptidase Clp
  • Amino Acyl-tRNA Synthetases
  • LARS2 protein, human