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Background <p>Over 200 pathogenic variants in the <i>OTOF</i> gene encoding otoferlin are associated with sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorders (ANSD).</p> Results <p>A novel splice variant, <i>OTOF</i> c.898-18G &gt; A, was detected in seven Jewish Moroccan families with both SNHL and ANSD in an Israeli multicenter study. The effect on splicing was confirmed by a minigene assay, which demonstrated skipping of exon 10. This variant is absent in gnomAD and in all Jewish ethnic groups except for Moroccan Jews, with a carrier rate of 1.5% in this ancestry, suggesting a founder effect.</p> Conclusions <p>The <i>OTOF</i> variant represents a second founder allele associated with hearing loss in the Moroccan Jewish community and may serve as a candidate for gene therapy.</p>

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A multicenter study reveals a novel pathogenic splice-site founder variant in OTOF

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Zippora Brownstein,
  • Lara Kamal,
  • Shir Mishan-Montefiori,
  • Yael Hoffman,
  • Dina Fine,
  • Yoel Hirsch,
  • Tzvi Weiden,
  • Rivka Birnbaum,
  • Hagar Mor-Shaked,
  • Bella Davidov,
  • Yuval Yaron,
  • Karen B. Avraham

摘要

Background

Over 200 pathogenic variants in the OTOF gene encoding otoferlin are associated with sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorders (ANSD).

Results

A novel splice variant, OTOF c.898-18G > A, was detected in seven Jewish Moroccan families with both SNHL and ANSD in an Israeli multicenter study. The effect on splicing was confirmed by a minigene assay, which demonstrated skipping of exon 10. This variant is absent in gnomAD and in all Jewish ethnic groups except for Moroccan Jews, with a carrier rate of 1.5% in this ancestry, suggesting a founder effect.

Conclusions

The OTOF variant represents a second founder allele associated with hearing loss in the Moroccan Jewish community and may serve as a candidate for gene therapy.