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Different Contribution of Missense and Loss-of-Function Variants to the Genetic Structure of Familial and Sporadic

Alberto M Parra-Perez1,2, Alvaro Gallego-Martinez1,2, Alba Escalera-Balsera1,2

  • 1Otology and Neurotology Group CTS495 Division of Otolaryngology Department of Surgery Instituto De Investigación Biosanitaria ibs.GRANADA Universidad De Granada Granada Spain.

Medcomm
|September 24, 2025
PubMed

Insights

This study reveals distinct genetic causes for Meniere disease (MD), differentiating familial (FMD) and sporadic (SMD) forms. While some genetic overlap exists, SMD may involve hidden inheritance patterns, suggesting complex genetic architectures for MD.

Area of Science:

  • Genetics
  • Otolaryngology
  • Molecular Biology

Background:

  • Meniere disease (MD) is a chronic, heritable inner ear disorder.
  • Understanding the genetic basis of sporadic MD (SMD) versus familial MD (FMD) is crucial for diagnosis and treatment.
  • Investigating rare variant burden can uncover genetic overlaps and differences between SMD and FMD.

Purpose of the Study:

  • To compare the burden of rare, high- and moderate-impact coding variants in SMD and FMD cohorts.
  • To determine genetic overlap between SMD and FMD, potentially identifying hidden inheritance in SMD.
  • To identify novel candidate genes associated with Meniere disease.

Main Methods:

  • Exome sequencing was performed on 93 FMD and 287 SMD patients.
  • Gene Burden Analysis (GBA) was used to identify enriched genes.
  • Candidate genes were prioritized based on variant carriers, inner-ear expression, and phenotype annotations.
  • Auditory brainstem responses in knockout mouse models were used to validate candidate genes.

Main Results:

  • Familial MD patients exhibited a higher accumulation of missense and loss-of-function variants, particularly in auditory and vestibular genes, compared to sporadic MD.
  • Gene Burden Analysis identified 269 enriched genes in SMD (31 inner ear-annotated) and 432 in FMD (51 inner ear-annotated).
  • A significant overlap (28.1%) of enriched genes was observed between SMD and FMD, with ADGRV1, MEGF8, and MYO7A being commonly shared.
  • Three novel Meniere disease candidate genes (NIN, CCDC88C, ANKRD24) were identified and validated using mouse models, showing hearing loss consistent with patient profiles.

Conclusions:

  • Sporadic and familial Meniere disease possess divergent genetic architectures.
  • The enrichment of variants in stria vascularis and hair cell stereocilia genes suggests distinct pathogenic mechanisms in MD.
  • Findings support a multiallelic-recessive inheritance pattern in Meniere disease, particularly in sporadic cases.
Keywords:
Meniere diseaseexome sequencinggenetic diagnosisgenomicsrare variant analysis

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