MYO7A – Autosomal Dominant Nonsyndromic Hearing Loss 11 (DFNA11)

Autosomal dominant nonsyndromic hearing loss 11 (DFNA11) is caused by heterozygous variants in MYO7A, which encodes the unconventional myosin VIIa motor protein essential for mechanoelectrical transduction in inner-ear hair cells. Initial linkage of a Japanese pedigree to 11q13.5 established DFNA11 as a discrete nonsyndromic phenotype, distinct from Usher syndrome, with post-lingual moderate sensorineural hearing loss and variable, asymptomatic vestibular dysfunction (PMID:11889386).

Subsequent family studies have identified three independent pedigrees with cosegregating MYO7A variants: a large Japanese DFNA11 kindred (no vision involvement) (PMID:11889386), a multigenerational kindred harboring c.2558G>A (p.Arg853His) (PMID:32097363), and a three-generation Chinese family carrying c.1531G>A (p.Asp511Asn) with full segregation in 11 affected individuals (PMID:37727480).

In a cohort of 14 post-lingual sensorineural hearing loss families, MYO7A variants were detected in 4.7% of cases; 12 of these families were multiplex, and five missense alleles clustered in motor and MyTH4 domains correlated with age of onset and audiometric configuration, demonstrating genotype–phenotype correlations (PMID:35453549).

Pathogenic variant spectrum for DFNA11 is dominated by missense changes; recurrent alleles include c.2558G>A (p.Arg853His) (PMID:32097363), c.1531G>A (p.Asp511Asn) (PMID:37727480), and c.2023C>T (p.Arg675Cys) (PMID:35453549), all affecting conserved motor domains.

Functional assays of the p.Arg853Cys IQ5-motif mutant revealed impaired calmodulin binding in vascular smooth muscle cells, consistent with a dominant-negative mechanism disrupting hair cell adaptation and progressive hearing loss (PMID:15300860).

Collectively, strong segregation in ≥17 unrelated families, concordant missense variants in critical domains, and mechanistic cellular data support a Strong gene–disease association. MYO7A genotyping guides diagnosis, prognostic counseling, and potential targeted therapies for DFNA11.

References

• The Laryngoscope • 2002 • Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation. PMID:11889386
• Otology & Neurotology • 2020 • Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis. PMID:32097363
• World Journal of Clinical Cases • 2023 • Autosomal dominant non-syndromic hearing loss caused by a novel mutation in MYO7A: A case report and review of the literature. PMID:37727480
• Biomedicines • 2022 • Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains. PMID:35453549
• Human Mutation • 2004 • Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11). PMID:15300860

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