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<p>Hearing loss (HL) is the most common sensory disability worldwide, with <i>GJB2-GJB6</i> connexin alterations (DFNB1) being the most frequent causes of non-syndromic hearing loss (NSHL). Recent studies have also highlighted the <i>STRC</i> gene as a significant contributor to NSHL, with its incidence potentially approaching that of connexin alterations. Despite advances in next-generation sequencing (NGS), molecular diagnosis remains challenging for many NSHL patients, often due to the complexity of analyzing the <i>STRC</i> gene. This is largely attributed to its location in a tandemly duplicated region and the presence of a homologous pseudogene (<i>STRCP1</i>), which complicates its accurate identification. The most common cause of DFNB16 is a homozygous large contiguous gene deletion at 15q15.3, but other copy number variants (CNVs), including both losses and gains, have been less well characterized. Through a combination of techniques we present new data on <i>STRC</i> variants and the diagnosis of 72 DFNB16 patients from 59 families. While the <i>CKMT1B-STRC-CATSPER2</i> deletion is the most frequent alteration, the improvement of droplet-digital PCR (ddPCR) for refining CNV analysis in the first 16 exons of the gene (99,8% homologous with the pseudogene) has allowed us to identify and better define a higher incidence of previously unclarified complex rearrangements. Additionally, we have identified a direct <i>cis</i> association between the c.4837 G &gt; T;p.(Glu1613*) pathogenic variant and the <i>CATSPER2-CKMT1A-STRCP1</i> duplication. These findings underscore the important role of ddPCR in identifying CNVs that are difficult to detect through conventional NGS, significantly improving diagnosis and enabling precise genetic counseling for affected families.</p>

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Refining the detection of complex rearrangements in 15q15.3 region involving the STRC gene in hereditary hearing loss patients

  • 期刊论文

  • 发表日期：

    2025年5月8日

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  • Sara Alvaro,
  • Daniel Castillo,
  • Jordi Genovés,
  • Erik D. Prados,
  • Maurizio Levorato,
  • Anna Albertí,
  • Águeda Díaz,
  • Sara Cardelús,
  • Loreto Martorell

摘要

Hearing loss (HL) is the most common sensory disability worldwide, with GJB2-GJB6 connexin alterations (DFNB1) being the most frequent causes of non-syndromic hearing loss (NSHL). Recent studies have also highlighted the STRC gene as a significant contributor to NSHL, with its incidence potentially approaching that of connexin alterations. Despite advances in next-generation sequencing (NGS), molecular diagnosis remains challenging for many NSHL patients, often due to the complexity of analyzing the STRC gene. This is largely attributed to its location in a tandemly duplicated region and the presence of a homologous pseudogene (STRCP1), which complicates its accurate identification. The most common cause of DFNB16 is a homozygous large contiguous gene deletion at 15q15.3, but other copy number variants (CNVs), including both losses and gains, have been less well characterized. Through a combination of techniques we present new data on STRC variants and the diagnosis of 72 DFNB16 patients from 59 families. While the CKMT1B-STRC-CATSPER2 deletion is the most frequent alteration, the improvement of droplet-digital PCR (ddPCR) for refining CNV analysis in the first 16 exons of the gene (99,8% homologous with the pseudogene) has allowed us to identify and better define a higher incidence of previously unclarified complex rearrangements. Additionally, we have identified a direct cis association between the c.4837 G > T;p.(Glu1613*) pathogenic variant and the CATSPER2-CKMT1A-STRCP1 duplication. These findings underscore the important role of ddPCR in identifying CNVs that are difficult to detect through conventional NGS, significantly improving diagnosis and enabling precise genetic counseling for affected families.