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Background <p>Sensorineural hearing impairment (SNHI) is a common disorder with a significant genetic basis. Standard next-generation sequencing (NGS) often fails to accurately identify pathogenic variants in the <i>STRC</i> gene due to its complex genomic structure, including large rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers improved resolution for these complex regions.</p> Methods <p>We developed a comprehensive workflow that integrates PacBio-based LRS with marker-mediated refinements and MLPA validations to specifically address pseudogene interference. This methodology was applied to analyze the <i>STRC</i> gene in a cohort of 100 unrelated Taiwanese patients with SNHI of unknown genetic origin after initial NGS screening.</p> Results <p>We identified bi-allelic <i>STRC</i> variants in 11 unrelated patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous single nucleotide variants (SNVs) and copy number variants (CNVs). All unrelated cases resolved with bi-allelic <i>STRC</i> variants were affected with mild or moderate SNHI, occupying 15.1% of total 73 mild-to-moderate SNHI patients in this study.</p> Conclusion <p>Our results highlight the diagnostic utility of this combined strategy, integrating LRS with marker-mediated refinements that validated by MLPA assays, in detecting complex <i>STRC</i> variants and advance the understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS approaches.</p> Graphical Abstract <p></p>

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Integrated analysis of STRC variants in hereditary hearing impairment using maker-mediated refinement of long-read sequencing with MLPA validation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月13日

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  • Cheng-Yu Tsai,
  • Yue-Sheng Lu,
  • Yu-Ting Chiang,
  • Ming-Yu Lo,
  • Pei-Hsuan Lin,
  • Shih-Feng Tsai,
  • Chuan-Jen Hsu,
  • Pei-Lung Chen,
  • Jacob Shu-Jui Hsu,
  • Chen-Chi Wu

摘要

Background

Sensorineural hearing impairment (SNHI) is a common disorder with a significant genetic basis. Standard next-generation sequencing (NGS) often fails to accurately identify pathogenic variants in the STRC gene due to its complex genomic structure, including large rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers improved resolution for these complex regions.

Methods

We developed a comprehensive workflow that integrates PacBio-based LRS with marker-mediated refinements and MLPA validations to specifically address pseudogene interference. This methodology was applied to analyze the STRC gene in a cohort of 100 unrelated Taiwanese patients with SNHI of unknown genetic origin after initial NGS screening.

Results

We identified bi-allelic STRC variants in 11 unrelated patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous single nucleotide variants (SNVs) and copy number variants (CNVs). All unrelated cases resolved with bi-allelic STRC variants were affected with mild or moderate SNHI, occupying 15.1% of total 73 mild-to-moderate SNHI patients in this study.

Conclusion

Our results highlight the diagnostic utility of this combined strategy, integrating LRS with marker-mediated refinements that validated by MLPA assays, in detecting complex STRC variants and advance the understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS approaches.

Graphical Abstract