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Background <p>Hearing loss (HL) is a highly heterogeneous condition with concerning statistics, particularly given the significant occurrence of consanguineous marriages in Iran. Despite the presence of variants of uncertain significance (VUS), high-yield prenatal screening remains unattainable. This article aims to discuss a VUS mutation as a potential cause of HL in a sibling, with the goal of reclassifying this variant.</p> Methods <p>This research examined a sibling with congenital HL. Their parents were first cousins, and no non-genetic factors for the disease were identified. Whole exome sequencing (WES) was conducted to ascertain the genetic etiology of the disease, subsequently validated by Sanger sequencing. The stability and interactions of the mutated protein were then evaluated.</p> Results <p>The homozygous variant <i>CDH23</i> (NM_022124.6) c.5149T &gt; C; p.C1717R has been suggested as the probable causative mutation. This variant was identified as a homozygous mutant in both patients and a heterozygous variant in healthy individuals. The mutation enhances the stability of this protein, whereas the interaction with the protein PCDH15, which plays a role in hemophilic stereocilia attachment, is entirely abolished in the areas surrounding the mutation. This protein interaction site is completely altered post-mutation, significantly reducing complex stability.</p> Conclusion <p>A homozygous variant in the <i>CDH23</i> gene was identified in two patients from the same pedigree as a consequence of this investigation. Consequently, in light of the findings of this investigation, it is advised that additional in silico studies, including molecular dynamics simulations and in vitro studies, be conducted to assist in the reclassification of this variant, thereby enabling more precise genetic counseling.</p>

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Discovering the pathogenesis of a VUS variant in CDH23 associated with sensorineural hearing loss in an Iranian family

  • 期刊论文

  • 发表日期：

    2025年3月6日

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  • Maryam Naghinejad,
  • Sima Mansoori Derakhshan,
  • Sepideh Parvizpour,
  • Akbar Amirfiroozy

摘要

Background

Hearing loss (HL) is a highly heterogeneous condition with concerning statistics, particularly given the significant occurrence of consanguineous marriages in Iran. Despite the presence of variants of uncertain significance (VUS), high-yield prenatal screening remains unattainable. This article aims to discuss a VUS mutation as a potential cause of HL in a sibling, with the goal of reclassifying this variant.

Methods

This research examined a sibling with congenital HL. Their parents were first cousins, and no non-genetic factors for the disease were identified. Whole exome sequencing (WES) was conducted to ascertain the genetic etiology of the disease, subsequently validated by Sanger sequencing. The stability and interactions of the mutated protein were then evaluated.

Results

The homozygous variant CDH23 (NM_022124.6) c.5149T > C; p.C1717R has been suggested as the probable causative mutation. This variant was identified as a homozygous mutant in both patients and a heterozygous variant in healthy individuals. The mutation enhances the stability of this protein, whereas the interaction with the protein PCDH15, which plays a role in hemophilic stereocilia attachment, is entirely abolished in the areas surrounding the mutation. This protein interaction site is completely altered post-mutation, significantly reducing complex stability.

Conclusion

A homozygous variant in the CDH23 gene was identified in two patients from the same pedigree as a consequence of this investigation. Consequently, in light of the findings of this investigation, it is advised that additional in silico studies, including molecular dynamics simulations and in vitro studies, be conducted to assist in the reclassification of this variant, thereby enabling more precise genetic counseling.