GSDME – Autosomal Dominant Nonsyndromic Hearing Loss

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is most frequently characterized by bilateral, symmetrical, postlingual progressive sensorineural impairment beginning at high frequencies and eventually involving all frequencies. Variants in GSDME, historically known as DFNA5, underlie the DFNA5 subtype of ADNSHL (MONDO:0019587). Pathogenic alleles uniformly disrupt splicing of exon 8, producing a truncated protein with toxic gain-of-function.

Genetic evidence comes from at least six unrelated families segregating ADNSHL, comprising over 120 affected individuals with autosomal dominant inheritance and complete co-segregation of GSDME splice variants with disease status (PMID:35864542; PMID:32486382; PMID:35054374). The recurrent 3-bp deletion c.991-15_991-13delTTC in intron 7 represents a founder variant in East Asians and a mutational hotspot in Europeans (PMID:32486382).

All reported pathogenic variants are splice-site or structural changes leading to exon 8 skipping. A key example is the novel heterozygous splice donor mutation c.1183+1G>C, which abolishes the intron 8 donor site and yields direct exon 7–9 joining in a six-generation Chinese pedigree (PMID:35864542). Copy number analyses in two additional families identified single-exon deletions (e.g., c.991-60_1095del) confirmed to ablate exon 8 by transcript studies (PMID:35054374).

Functional assays robustly support a gain-of-function mechanism. Minigene splicing experiments demonstrate complete exon 8 exclusion for all splice variants. Mammalian cell transfection of mutant DFNA5-GFP constructs doubles necrotic cell death compared with wild type, implicating the N-terminal fragment as cytotoxic (PMID:15173223). Homozygous Dfna5 knockout mice recapitulating exon 8 deletion show altered cochlear outer hair cell counts but no overt hearing loss, highlighting species-specific effects (PMID:16023581).

No reports to date demonstrate loss-of-function alleles causing ADNSHL or alternative phenotypes, and epigenetic silencing in cancer does not produce hearing impairment. Together, the genetic and experimental data fulfill strong ClinGen criteria for ADNSHL due to GSDME, with all variants converging on exon 8 skipping and downstream cytotoxicity.

Key take-home: GSDME variants cause autosomal dominant nonsyndromic hearing loss through a consistent exon 8 skipping gain-of-function mechanism, enabling precise genetic diagnosis and guiding functional assays and therapeutic research.

References

• BMC medical genomics • 2022 • A novel splice site variant c.1183+1G>C in DFNA5 causing autosomal dominant nonsyndromic hearing loss in a Chinese family. PMID:35864542
• International Journal of Molecular Sciences • 2020 • DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? PMID:32486382
• Diagnostics (Basel, Switzerland) • 2022 • Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss. PMID:35054374
• Journal of Medical Genetics • 2004 • DFNA5: hearing impairment exon instead of hearing impairment gene? PMID:15173223
• Neurobiology of Disease • 2005 • Mice lacking Dfna5 show a diverging number of cochlear fourth row outer hair cells. PMID:16023581

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