Biallelic mutations in pakistani families with autosomal recessive prelingual nonsyndromic hearing loss

Genes Genomics. 2023 Feb;45(2):145-156. doi: 10.1007/s13258-022-01349-3. Epub 2022 Dec 6.


Background: Nonsyndromic autosomal recessive hearing loss (DFNB) is an etiologically heterogeneous disorder group showing a wide spectrum of onset ages and severity. DFNB genes are very diverse in their types and functions, making molecular diagnosis difficult. DFNB is particularly frequent in Pakistan, which may be partly due to consanguinity.

Objective: This study was performed to determine the genetic causes in Pakistani DFNB families with prelingual onset and to establish genotype-phenotype correlation.

Methods: Whole exome sequencing and subsequent genetic analysis were performed for 11 Pakistani DFNB families including eight consanguineous families.

Results: We identified eight pathogenic or likely pathogenic mutations in LOXHD1, GJB2, SLC26A4, MYO15A, and TMC1 from six families. The GJB2 mutations were identified in two families each with compound heterozygous mutations and a homozygous mutation. The compound heterozygous mutations in LOXHD1 ([p.D278Y] + [p.D1219E]) and GJB2 [p.M1?] + [p.G12Vfs*2]) were novel. The four missense or start-loss mutations were located at well conserved residues, and most in silico analysis predicted their pathogenicity. In addition to causative mutations, we found compound heterozygous mutations in PTPRQ as variants of uncertain significance.

Conclusion: This study identified biallelic mutations as the underlying cause of early onset DFNB in six Pakistani families. This study will be helpful in providing an exact molecular diagnosis and treatment of prelingual onset deafness patients.

Keywords: Autosomal recessive hearing loss (DFNB); GJB2; LOXHD1; MYO15A; Pakistan; SLC26A4; TMC1.

MeSH terms

  • Deafness* / genetics
  • Homozygote
  • Humans
  • Mutation
  • Pakistan
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics


  • PTPRQ protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3

Supplementary concepts

  • Nonsyndromic Deafness