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Background <p>Hearing loss (HL) is one of the most common sensorineural disorders, affecting 5% of the world’s population. Despite advances in next-generation sequencing (NGS) platforms, the diagnosis of HL remains challenging because of its vast genetic heterogeneity. This study aimed to improve the diagnosis of HL through re-evaluation and new Exome Sequencing (ES) of undiagnosed Iranian HL families.</p> Methods and results <p>We conducted a systematic ES data reanalysis of old cases and new ES in second family members, 5–9 years after the initial analysis of four consanguineous Iranian non-syndromic hearing loss (NSHL) families, which revealed negative results previously using <i>GJB2</i> screening, an OtoSCOPE panel (V5 and V6), and ES analysis. After a clinician-led reanalysis of the ES data and comprehensive bioinformatics analysis, segregation analysis of potential candidate variants was performed by Sanger sequencing using an ABI 3500 sequencer. Our study revealed four novel variants, including two in known HL-associated genes (<i>OTOA</i> and <i>TBC1D24</i>) and two in candidate genes (<i>DBX2</i> and <i>ARHGAP22</i>). These variants co-segregated in the pedigrees, suggesting their potential role in HL.</p> Conclusion <p>Our findings highlight the importance of combining ES for second family members with periodic reanalysis of existing data. This approach not only improves variant detection but also facilitates more accurate genetic counseling and potential targeted interventions for hereditary HL.</p>

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Combining re-evaluation and new exome sequencing to identify novel genetic variants and candidate genes in Iranian families with non-syndromic hearing loss

  • 期刊论文

  • 发表日期：

    2025年12月18日

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  • Raziye Rezvani Rezvandeh,
  • Negar Kazemi,
  • Farzane Zare Ashrafi,
  • Ebrahim Shokouhian,
  • Zahra Bolghanabadi,
  • Mohammad Amin Omrani,
  • Masoud Edizadeh,
  • Kimia Kahrizi,
  • Hossein Najmabadi,
  • Marzieh Mohseni

摘要

Background

Hearing loss (HL) is one of the most common sensorineural disorders, affecting 5% of the world’s population. Despite advances in next-generation sequencing (NGS) platforms, the diagnosis of HL remains challenging because of its vast genetic heterogeneity. This study aimed to improve the diagnosis of HL through re-evaluation and new Exome Sequencing (ES) of undiagnosed Iranian HL families.

Methods and results

We conducted a systematic ES data reanalysis of old cases and new ES in second family members, 5–9 years after the initial analysis of four consanguineous Iranian non-syndromic hearing loss (NSHL) families, which revealed negative results previously using GJB2 screening, an OtoSCOPE panel (V5 and V6), and ES analysis. After a clinician-led reanalysis of the ES data and comprehensive bioinformatics analysis, segregation analysis of potential candidate variants was performed by Sanger sequencing using an ABI 3500 sequencer. Our study revealed four novel variants, including two in known HL-associated genes (OTOA and TBC1D24) and two in candidate genes (DBX2 and ARHGAP22). These variants co-segregated in the pedigrees, suggesting their potential role in HL.

Conclusion

Our findings highlight the importance of combining ES for second family members with periodic reanalysis of existing data. This approach not only improves variant detection but also facilitates more accurate genetic counseling and potential targeted interventions for hereditary HL.