Integrated analysis of STRC variants in hereditary hearing impairment using maker-mediated refinement of long-read sequencing with MLPA validation
- 1Department of Otolaryngology, National Taiwan University Hospital
- 2Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University
- 3Institute of Molecular and Genomic Medicine, National Health Research Institute
Abstract
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
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BibTeX
@article{tsai2026integrated,
title = {{Integrated analysis of STRC variants in hereditary hearing impairment using maker-mediated refinement of long-read sequencing with MLPA validation}},
author = {Cheng-Yu Tsai and Yue-Sheng Lu and Yu-Ting Chiang and Ming-Yu Lo and Pei-Hsuan Lin and Shih-Feng Tsai and Chuan-Jen Hsu and Pei-Lung Chen and Jacob Shu-Jui Hsu and Chen-Chi Wu},
journal = {Molecular Medicine},
year = {2026},
month = jul,
doi = {10.1186/s10020-026-01553-x},
url = {https://doi.org/10.1186/s10020-026-01553-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrated analysis of STRC variants in hereditary hearing impairment using maker-mediated refinement of long-read sequencing with MLPA validation
AU - Cheng-Yu Tsai
AU - Yue-Sheng Lu
AU - Yu-Ting Chiang
AU - Ming-Yu Lo
AU - Pei-Hsuan Lin
AU - Shih-Feng Tsai
AU - Chuan-Jen Hsu
AU - Pei-Lung Chen
AU - Jacob Shu-Jui Hsu
AU - Chen-Chi Wu
PY - 2026
DA - 2026/07/01
JO - Molecular Medicine
DO - 10.1186/s10020-026-01553-x
UR - https://doi.org/10.1186/s10020-026-01553-x
AB - 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
SN - 1528-3658
SN - 1076-1551
ER -