DIAPH1 – Autosomal Dominant Nonsyndromic Hearing Loss 1

Autosomal dominant variants in DIAPH1 underlie DFNA1, characterized by progressive sensorineural hearing loss beginning in childhood. The association is supported by multiple unrelated families carrying heterozygous truncating mutations in the diaphanous autoregulatory domain (DAD) of DIAPH1, consistent segregation, and convergent functional data demonstrating constitutive formin activation and cochlear pathology.

Clinical Validity (Strong)

The DIAPH1–DFNA1 association meets ClinGen Strong criteria: two unrelated families with heterozygous truncating DAD mutations segregating with hearing loss ([PMID:27707755]) and replication in independent case reports. Functional models corroborate pathogenicity, without contradictory evidence.

Genetic Evidence (Strong)

Inheritance is autosomal dominant. Segregation analysis in two DFNA1 pedigrees revealed co-segregation of DAD-truncating alleles with hearing loss, involving multiple affected individuals across generations ([PMID:27707755]). Case reports describe additional heterozygous DIAPH1 variants—c.1589T>G (p.Ile530Ser) in a Korean family ([PMID:28003573]), c.793G>T (p.Ala265Ser) in DID domain mutants ([PMID:31473629]), and c.3145C>T (p.Arg1049Ter) in late-onset hearing loss ([PMID:35060117])—expanding the variant spectrum. Variant classes include C-terminal truncations and N-terminal missense substitutions disrupting autoinhibition.

Functional Evidence (Strong)

Truncating DAD mutants disrupt the DID–DAD interaction, leading to constitutive mDia1 activation, increased actin polymerization, and elongated microvilli in vitro ([PMID:27707755]). Mouse models expressing FLAG-tagged DIAPH1(R1204X) recapitulate progressive deafness, hair cell loss at the basal cochlear turn, and stereocilia abnormalities, confirming a gain-of-function mechanism.

Integration & Clinical Utility

Collectively, dominant DIAPH1 mutations that truncate the DAD relieve autoinhibition, causing aberrant actin dynamics in hair cells and sensorineural hearing loss. Genetic testing for DIAPH1 truncations and key missense alleles informs diagnosis, prognosis, and genetic counselling. Functional assays validate pathogenicity, supporting targeted therapeutic exploration.

Key Take-home: Gain-of-function truncations in DIAPH1 cause DFNA1 via disruption of autoinhibitory regulation, offering a clear genetic and mechanistic basis for diagnostic and research applications.

References

• EMBO Mol Med • 2016 • Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss. PMID:27707755
• Genes & Genet Syst • 2017 • A novel missense variant in the DIAPH1 gene in a Korean family with autosomal dominant nonsyndromic hearing loss. PMID:28003573
• J Med Genet • 2019 • Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human DIAPH1-related cytoskeletopathy. PMID:31473629
• Clin Genet • 2022 • Late-onset hearing loss case associated with a heterozygous truncating variant of DIAPH1. PMID:35060117

Evidence Based Scoring (AI generated)