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<p>Hearing loss exhibits significant clinical and genetic heterogeneity. More than 50% of Hearing loss cases have a genetic etiology. In terms of genetics,, hearing loss can be classified as either syndromic or non-syndromic. It has been demonstrated that over 100 genes and 1,000 associated mutations are involved in hearing loss that can be inherited through autosomal recessive, autosomal dominant, X-linked, or mitochondrial mechanisms This vast genetic heterogeneity has posed a significant challenge for genetic researchers in identifying the specific mutated gene in affected individuals from diverse ethnic backgrounds. However, recent advancements in next-generation sequencing technologies, particularly whole-exome sequencing (WES), have facilitated the identification of mutated genes in individuals with deafness.&#xa0;The primary objective of this study was to employ whole-exome sequencing (WES) to ascertain the genetic underpinnings of non-syndromic hearing loss in a Kurdish consanguineous family and to examine the associated clinical manifestations of the identified genetic mutation.&#xa0;A cohort of fifteen affected (fourteen with prelingual and one with postlingual hearing loss) and fifteen unaffected individuals from a Kurdish family was enrolled in this study. A comprehensive evaluation was conducted, encompassing meticulous physical examinations and audiometric assessments, to ascertain the presence of hearing impairment among the affected participants. Genomic DNA was extracted from blood samples and subjected to whole-exome sequencing. Subsequent variant identification and annotation were conducted to identify potential pathogenic mutations. To corroborate the finding of whole-exome sequencing (WES), a polymerase chain reaction (PCR) was performed on the flanking region encompassing the identified variant. Subsequent Sanger sequencing of the PCR product verified the presence of the WES-derived variant. The variant was than investigated in additional affected families through Sanger sequencing and restriction fragment length polymorphism (RFLP)-PCR analysis.&#xa0;A thorough analysis of whole-exome sequencing data led to the identification of a pathogenic c.1180&#xa0;C &gt; T variant (NM_198159.3) in the <i>MITF</i> gene, which is likely to be a causative factor for non-syndromic hearing loss in this family. This particular nucleotide substitution leads to the formation of a premature stop codon at amino acid position 394 (p. Arg394Ter, NP_937802.1) of the MITF protein. It is predicted that this will result in a truncated and potentially non-functional protein product. The identified pathogenic variant was detected in a heterozygous state in 13 of the affected individuals, which is consistent with an autosomal dominant inheritance pattern. However, the pathogenic variant was also detected in a homozygous state in 2 individuals. Also, in examining the clinical manifestations of this mutation, no notable differences were observed between homozygous and heterozygous individuals.&#xa0;The c.1180C&gt;T variant in <i>MITF</i> (NM_198159.3), previously reported in ClinVar (Variation ID: 995923) as pathogenic for Waardenburg syndrome type 2A, was identified. Unlike prior reports associating this variant with a broad spectrum of symptoms, including pigmentation abnormalities, our study found it to be linked solely to hearing loss in this population. Notably, no differences in clinical manifestations were observed between homozygous and heterozygous individuals, suggesting population-specific factors may influence the phenotypic expression of this variant.</p>

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Whole-Exome Sequencing Identified a Nonsense Pathogenic Variant in the MITF Gene Associated with Non-syndromic Hearing Loss

  • 期刊论文

  • 发表日期：

    2025年11月27日

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  • Farzad Soleimani,
  • Arash Pooladi,
  • Masoud Alasvand,
  • Golaleh Karbasi,
  • Fardin Fathi

摘要

Hearing loss exhibits significant clinical and genetic heterogeneity. More than 50% of Hearing loss cases have a genetic etiology. In terms of genetics,, hearing loss can be classified as either syndromic or non-syndromic. It has been demonstrated that over 100 genes and 1,000 associated mutations are involved in hearing loss that can be inherited through autosomal recessive, autosomal dominant, X-linked, or mitochondrial mechanisms This vast genetic heterogeneity has posed a significant challenge for genetic researchers in identifying the specific mutated gene in affected individuals from diverse ethnic backgrounds. However, recent advancements in next-generation sequencing technologies, particularly whole-exome sequencing (WES), have facilitated the identification of mutated genes in individuals with deafness. The primary objective of this study was to employ whole-exome sequencing (WES) to ascertain the genetic underpinnings of non-syndromic hearing loss in a Kurdish consanguineous family and to examine the associated clinical manifestations of the identified genetic mutation. A cohort of fifteen affected (fourteen with prelingual and one with postlingual hearing loss) and fifteen unaffected individuals from a Kurdish family was enrolled in this study. A comprehensive evaluation was conducted, encompassing meticulous physical examinations and audiometric assessments, to ascertain the presence of hearing impairment among the affected participants. Genomic DNA was extracted from blood samples and subjected to whole-exome sequencing. Subsequent variant identification and annotation were conducted to identify potential pathogenic mutations. To corroborate the finding of whole-exome sequencing (WES), a polymerase chain reaction (PCR) was performed on the flanking region encompassing the identified variant. Subsequent Sanger sequencing of the PCR product verified the presence of the WES-derived variant. The variant was than investigated in additional affected families through Sanger sequencing and restriction fragment length polymorphism (RFLP)-PCR analysis. A thorough analysis of whole-exome sequencing data led to the identification of a pathogenic c.1180 C > T variant (NM_198159.3) in the MITF gene, which is likely to be a causative factor for non-syndromic hearing loss in this family. This particular nucleotide substitution leads to the formation of a premature stop codon at amino acid position 394 (p. Arg394Ter, NP_937802.1) of the MITF protein. It is predicted that this will result in a truncated and potentially non-functional protein product. The identified pathogenic variant was detected in a heterozygous state in 13 of the affected individuals, which is consistent with an autosomal dominant inheritance pattern. However, the pathogenic variant was also detected in a homozygous state in 2 individuals. Also, in examining the clinical manifestations of this mutation, no notable differences were observed between homozygous and heterozygous individuals. The c.1180C>T variant in MITF (NM_198159.3), previously reported in ClinVar (Variation ID: 995923) as pathogenic for Waardenburg syndrome type 2A, was identified. Unlike prior reports associating this variant with a broad spectrum of symptoms, including pigmentation abnormalities, our study found it to be linked solely to hearing loss in this population. Notably, no differences in clinical manifestations were observed between homozygous and heterozygous individuals, suggesting population-specific factors may influence the phenotypic expression of this variant.