Comprehensive genetic analysis of STRC variants in hereditary hearing impairment using long-read sequencing

Abstract

BackgroundSensorineural hearing impairment (SNHI) is a common disorder with a significant genetic component. Genetic testing for SNHI often involves next-generation sequencing (NGS), but SNHI-related pathogenic STRC variants cannot be directly addressed by conventional NGS due to the complex genomic scenario derived from large genomic rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers an unprecedented resolution to these challenges. MethodsWe developed a comprehensive workflow that integrates the PacBio-based LRS approach with marker-mediated refinements to effectively address pseudogene contamination. This methodology was applied to analyze the STRC gene in a cohort of 100 unrelated Taiwanese patients diagnosed with SNHI of unknown genetic cause after first-tier NGS testing. ResultsWe identified bi-allelic STRC variants in 11 patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous SNVs and CNVs. In total, we detected STRC variants in 27 patients, with 81.6% of these variants occurring in patients with mild to moderate SNHI. ConclusionsThis study represents the first large-scale clinical investigation utilizing LRS technology for the genetic diagnosis of SNHI. Our study highlights the diagnostic capabilities of LRS in detecting complex variants within the STRC and advancing our understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/24316795v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1fae5aforg.highwire.dtl.DTLVardef@fd6d2eorg.highwire.dtl.DTLVardef@b18c1org.highwire.dtl.DTLVardef@86364f_HPS_FORMAT_FIGEXP M_FIG C_FIG