Identification of homozygous missense variant in SIX5 gene underlying recessive nonsyndromic hearing impairment

PLoS One. 2022 Jun 16;17(6):e0268078. doi: 10.1371/journal.pone.0268078. eCollection 2022.


Hearing impairment (HI) is a heterogeneous condition that affects many individuals globally with different age groups. HI is a genetically and phenotypically heterogeneous disorder. Over the last several years, many genes/loci causing rare autosomal recessive and dominant forms of hearing impairments have been identified, involved in various aspects of ear development. In the current study, two affected individuals of a consanguineous family exhibiting autosomal recessive nonsyndromic hearing impairment (AR-NSHI) were clinically and genetically characterized. The single affected individual (IV-2) of the family was subjected to whole-exome sequencing (WES) accompanied by traditional Sanger sequencing. Clinical examinations using air conduction audiograms of both the affected individuals showed profound hearing loss across all frequencies. WES revealed a homozygous missense variant (c.44G>C) in the SIX5 gene located on chromosome 19q13.32. We report the first case of autosomal recessive NSHI due to a biallelic missense variant in the SIX5 gene. This report further supports the evidence that the SIX5 variant might cause profound HI and supports its vital role in auditory function. Identification of novel candidate genes might help in application of future gene therapy strategies that may be implemented for NSHI, such as gene replacement using cDNA, gene silencing using RNA interference, and gene editing using the CRISPR/Cas9 system.

Publication types

  • Case Reports

MeSH terms

  • Deafness* / genetics
  • Genes, Recessive
  • Hearing Loss* / genetics
  • Hearing Loss, Sensorineural* / genetics
  • Homozygote
  • Humans
  • Mutation
  • Mutation, Missense
  • Pedigree

Supplementary concepts

  • Nonsyndromic Deafness

Grants and funding

The author(s) received no specific funding for this work.