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Background <p>Hearing loss (HL) is one of the most common congenital conditions and exhibits substantial clinical and genetic heterogeneity. More than 150 genes are associated with non-syndromic hearing loss (NSHL), while over 600 genes are linked to syndromic hearing loss (SHL). Importantly, the absence of additional clinical symptoms at the time of diagnosis does not necessarily exclude SHL. An increasing number of functionally disruptive variants in a growing number of genes have been shown to initially present as isolated HL, only later revealing syndromic features.</p> Methods <p>We analyzed clinical data from 111 patients across 102 unrelated families, selected from over 600 individuals negative for <i>GJB2</i> and <i>STRC</i> variants. Molecular inversion probe panel, exome, or genome sequencing was performed, and patients were retrospectively divided into three subgroups following variant interpretation. Molecular docking was performed on select non-synonymous substitutions.</p> Results <p>Subgroup 1 included 30 patients with variants in neurodevelopmental disorder (NDD)-associated genes. HL was the first clinical manifestation in 80% of patients, with it being the sole first symptom in half. Subgroup 2 was comprised of 52 patients with variants in SHL-associated genes unrelated to NDD, while subgroup 3 included 29 patients with variants in genes associated with both NSHL and SHL, such as <i>SLC26A4</i> and <i>USH1C</i>. In subgroups 2 and 3, HL was the sole initial symptom for nearly all patients (92% and 100%, respectively). Across the cohort, 99 variants in 44 genes were identified, including 36 novel variants.</p> Conclusion <p>The frequent absence of syndromic features at presentation may lead to genetic testing or analysis restricted to NSHL-associated genes. Our findings highlight the critical role of comprehensive genomic testing in the diagnostic workup of HL, enabling earlier identification of syndromic forms and facilitating timely medical management, genetic counseling, and anticipatory care.</p>

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Clinical and genetic heterogeneity of syndromic hearing loss and its non-syndromic hearing loss mimics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月7日

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  • Asuman Koparir,
  • Paulina Bahena Carbajal,
  • Mina Zamini,
  • Maryam Naghinejad,
  • Paria Najarzadeh Torbati,
  • Michaela A. H. Hofrichter,
  • Stefanie Tovornik,
  • Erkan Koparir,
  • Neda Dragicevic Babic,
  • Aboulfazl Rad,
  • Daniel Owrang,
  • Irem Kalay,
  • Niloofar Chamanrou,
  • Luis Nicolás Martínez Völter,
  • Nele Christophersen,
  • Tayebeh Baranzehi,
  • Mohsen Rajati,
  • Stephen Loum,
  • Erdmute Kunstmann,
  • Madiha Shadab,
  • Ansar Ahmed Abbasi,
  • Mohammad Doosti,
  • Neda Alidadiani,
  • Shahrooz Ghaderi,
  • Tobias B. Haack,
  • Shahryar Alavi,
  • Julia Doll,
  • Hannie Kremer,
  • Dor Mohammad Kordi-Tamandani,
  • David Murphy,
  • Rahema Mohammad,
  • Helge Hebestreit,
  • Ehsan Ghayoor Karimiani,
  • Sophie Flandin,
  • Paola Linares,
  • Daniel Villalobos,
  • Henry Houlden,
  • Hamid Galehdari,
  • Wafaa Shehata-Dieler,
  • Reza Maroofian,
  • Thomas Haaf,
  • Barbara Vona

摘要

Background

Hearing loss (HL) is one of the most common congenital conditions and exhibits substantial clinical and genetic heterogeneity. More than 150 genes are associated with non-syndromic hearing loss (NSHL), while over 600 genes are linked to syndromic hearing loss (SHL). Importantly, the absence of additional clinical symptoms at the time of diagnosis does not necessarily exclude SHL. An increasing number of functionally disruptive variants in a growing number of genes have been shown to initially present as isolated HL, only later revealing syndromic features.

Methods

We analyzed clinical data from 111 patients across 102 unrelated families, selected from over 600 individuals negative for GJB2 and STRC variants. Molecular inversion probe panel, exome, or genome sequencing was performed, and patients were retrospectively divided into three subgroups following variant interpretation. Molecular docking was performed on select non-synonymous substitutions.

Results

Subgroup 1 included 30 patients with variants in neurodevelopmental disorder (NDD)-associated genes. HL was the first clinical manifestation in 80% of patients, with it being the sole first symptom in half. Subgroup 2 was comprised of 52 patients with variants in SHL-associated genes unrelated to NDD, while subgroup 3 included 29 patients with variants in genes associated with both NSHL and SHL, such as SLC26A4 and USH1C. In subgroups 2 and 3, HL was the sole initial symptom for nearly all patients (92% and 100%, respectively). Across the cohort, 99 variants in 44 genes were identified, including 36 novel variants.

Conclusion

The frequent absence of syndromic features at presentation may lead to genetic testing or analysis restricted to NSHL-associated genes. Our findings highlight the critical role of comprehensive genomic testing in the diagnostic workup of HL, enabling earlier identification of syndromic forms and facilitating timely medical management, genetic counseling, and anticipatory care.