Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss

Mol Genet Genomic Med. 2020 Dec;8(12):e1550. doi: 10.1002/mgg3.1550. Epub 2020 Nov 18.


Background: Hereditary hearing loss (HL) is a heterogeneous and most common sensory neural disorder. At least, 76 genes have been reported in association with autosomal recessive nonsyndromic HL (ARNSHL). Herein, we subjected two patients with bilateral sensorineural HL in two distinct consanguineous Iranian families to figure out the underlying genetic factors.

Methods: Physical and sensorineural examinations were performed on the patients. Imaging also was applied to unveil any abnormalities in anatomical structures of the middle and inner ear. In order to decipher the possible genetic causes of the verified GJB2-negative samples, the probands were subjected to whole-exome sequencing and, subsequently, Sanger sequencing was applied for variant confirmation.

Results: Clinical examinations showed ARNSHL in the patients. After doing whole exome sequencing, two novel variants were identified that were co-segregating with HL that were absent in 100 ethnically matched controls. In the first family, a novel homozygous variant, NM_138691.2: c.530T>C; p.(lle177Thr), in TMC1 gene co-segregated with prelingual ARNSHL. In the second family, NM_022124.6: c.2334G>A; p.(Trp778*) was reported as a nonsense variant causing prelingual ARNSHL.

Conclusion: These findings can, in turn, endorse how TMC1 and CDH23 screening is critical to detecting HL in Iranian patients. Identifying TMC1 and CDH23 pathogenic variants doubtlessly help in the detailed genotypic characterization of HL.

Keywords: cadherin 23; deafness; transmembrane channel-like 1; whole-exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Cadherin Related Proteins
  • Cadherins / genetics*
  • Child
  • Female
  • Genes, Recessive
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / pathology
  • Homozygote
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Mutation*
  • Pedigree


  • CDH23 protein, human
  • Cadherin Related Proteins
  • Cadherins
  • Membrane Proteins
  • TMC1 protein, human

Supplementary concepts

  • Nonsyndromic sensorineural hearing loss