Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population

J Adv Res. 2021 Jan 12;31:13-24. doi: 10.1016/j.jare.2021.01.005. eCollection 2021 Jul.


Introduction: Hearing impairment (HI) is characterized by complex genetic heterogeneity. The evolution of next generation sequencing, including targeted enrichment panels, has revolutionized HI diagnosis.

Objectives: In this study, we investigated genetic causes in 22 individuals with non-GJB2 HI.

Methods: We customized a HaloplexHS kit to include 30 genes known to be associated with autosomal recessive nonsyndromic HI (ARNSHI) and Usher syndrome in North Africa.

Results: In accordance with the ACMG/AMP guidelines, we report 11 pathogenic variants; as follows; five novel variants including three missense (ESRRB-Tyr295Cys, MYO15A-Phe2089Leu and MYO7A-Tyr560Cys) and two nonsense (USH1C-Gln122Ter and CIB2-Arg104Ter) mutations; two previously reported mutations (OTOF-Glu57Ter and PNPT1-Glu475Gly), but first time identified among Tunisian families; and four other identified mutations namely WHRN-Gly808AspfsX11, SLC22A4-Cys113Tyr and two MYO7A compound heterozygous splice site variants that were previously described in Tunisia. Pathogenic variants in WHRN and CIB2 genes, in patients with convincing phenotype ruling out retinitis pigmentosa, provide strong evidence supporting their association with ARNSHI. Moreover, we shed lights on the pathogenic implication of mutations in PNPT1 gene in auditory function providing new evidence for its association with ARNSHI. Lack of segregation of a previously identified causal mutation OTOA-Val603Phe further supports its classification as variant of unknown significance. Our study reports absence of otoacoustic emission in subjects using bilateral hearing aids for several years indicating the importance of screening genetic alteration in OTOF gene for proper management of those patients.

Conclusion: In conclusion, our findings do not only expand the spectrum of HI mutations in Tunisian patients, but also improve our knowledge about clinical relevance of HI causing genes and variants.

Keywords: Diagnosis; Genetic heterogeneity; Hearing impairment; Next generation sequencing; Pathogenic variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child, Preschool
  • Deafness / diagnosis
  • Deafness / genetics
  • Exoribonucleases
  • Female
  • Genetic Heterogeneity
  • Genetic Testing / methods
  • Hearing Loss / diagnosis*
  • Hearing Loss / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Membrane Proteins
  • Mutation
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Tunisia
  • Usher Syndromes / diagnosis
  • Usher Syndromes / genetics
  • Young Adult


  • Membrane Proteins
  • OTOF protein, human
  • Exoribonucleases
  • PNPT1 protein, human

Supplementary concepts

  • Nonsyndromic Deafness