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Background <p>Congenital hearing loss is a common and genetically diverse sensory disorder. Non-syndromic forms are often inherited in an autosomal recessive pattern, with the types and frequencies of clinically relevant variants differing across populations. Studies of consanguineous families have been instrumental in identifying genes associated with autosomal recessive non-syndromic hearing loss (ARNSHL). The present study aimed to characterize candidate variants potentially underlying ARNSHL in seven unrelated Iranian families with consanguinity or from the same geographic region, as reported during genetic counseling.</p> Methods <p>We conducted <i>GJB2</i> screening, whole-exome sequencing (WES), and copy-number variation (CNV) analysis in seven probands with sensorineural hearing loss in the absence of additional phenotypes. Bioinformatic filtering, in silico analysis, and segregation studies were applied to determine the potential clinical relevance of candidate variants.</p> Results <p>WES identified nine different candidate variants in five genes among the probands and their affected family members, including six missense variants, two affecting canonical splice sites, and one nonsense variant. Previously reported variants included <i>TMC1</i> (NM_138691.3:c.100&#xa0;C &gt; T), <i>SLC26A4</i> (NM_000441.2:c.1229&#xa0;C &gt; T, c.716T &gt; A, c.2027T &gt; A), <i>MYO7A</i> (NM_000260.4:c.247&#xa0;C &gt; T), <i>LOXHD1</i> (NM_001384474.1:c.4940&#xa0;C &gt; A), and <i>CABP2</i> (NM_016366.3:c.637 + 1G &gt; T). Additionally, two novel variants were detected in two unrelated families: <i>LOXHD1</i> (NM_001384474.1:c.1136T &gt; A) and <i>TMC1</i> (NM_138691.3:c.1567-1G &gt; A).</p> Conclusion <p>This study contributes to the current understanding of the genetic spectrum of ARNSHL in a small cohort of Iranian families by identifying rare variants in known hearing loss genes, including a novel missense variant in <i>LOXHD1</i> and a novel splice-site variant in <i>TMC1</i>. However, due to lack of functional validation, their clinical significance remains uncertain. Further functional and large-cohort studies are needed to confirm pathogenicity and clarify genotype–phenotype relationships.</p>

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Molecular diagnosis of non-syndromic hearing loss in seven Iranian families using whole-exome sequencing

  • 期刊论文

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  • 发表日期：

    2026年6月2日

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  • Fateme Zahedi Abghari,
  • Emran Esmaeilzadeh,
  • Sajjad Biglari,
  • Hossein Ghasemi,
  • Marzieh Mohseni,
  • Narges Shahmohammad,
  • Hamid Reza Khorram Khorshid,
  • Reza Najafipour

摘要

Background

Congenital hearing loss is a common and genetically diverse sensory disorder. Non-syndromic forms are often inherited in an autosomal recessive pattern, with the types and frequencies of clinically relevant variants differing across populations. Studies of consanguineous families have been instrumental in identifying genes associated with autosomal recessive non-syndromic hearing loss (ARNSHL). The present study aimed to characterize candidate variants potentially underlying ARNSHL in seven unrelated Iranian families with consanguinity or from the same geographic region, as reported during genetic counseling.

Methods

We conducted GJB2 screening, whole-exome sequencing (WES), and copy-number variation (CNV) analysis in seven probands with sensorineural hearing loss in the absence of additional phenotypes. Bioinformatic filtering, in silico analysis, and segregation studies were applied to determine the potential clinical relevance of candidate variants.

Results

WES identified nine different candidate variants in five genes among the probands and their affected family members, including six missense variants, two affecting canonical splice sites, and one nonsense variant. Previously reported variants included TMC1 (NM_138691.3:c.100 C > T), SLC26A4 (NM_000441.2:c.1229 C > T, c.716T > A, c.2027T > A), MYO7A (NM_000260.4:c.247 C > T), LOXHD1 (NM_001384474.1:c.4940 C > A), and CABP2 (NM_016366.3:c.637 + 1G > T). Additionally, two novel variants were detected in two unrelated families: LOXHD1 (NM_001384474.1:c.1136T > A) and TMC1 (NM_138691.3:c.1567-1G > A).

Conclusion

This study contributes to the current understanding of the genetic spectrum of ARNSHL in a small cohort of Iranian families by identifying rare variants in known hearing loss genes, including a novel missense variant in LOXHD1 and a novel splice-site variant in TMC1. However, due to lack of functional validation, their clinical significance remains uncertain. Further functional and large-cohort studies are needed to confirm pathogenicity and clarify genotype–phenotype relationships.