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MYO7A encodes the unconventional myosin VIIA motor protein, which is crucial for mechanotransduction in inner ear hair cells and cargo transport in retinal pigment epithelium. Mutations in MYO7A underlie Usher syndrome type 1B, a form of Usher syndrome (an autosomal recessive deaf-blindness disorder) characterized by congenital profound sensorineural hearing loss, constant vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. The association between MYO7A and Usher syndrome is well established through linkage to USH1B on chromosome 11q13.5 and mutation screening across diverse populations.
Inheritance: Autosomal recessive
Multiple independent studies report biallelic pathogenic variants in MYO7A segregating with classic USH1 phenotype in unrelated families. A panel of 189 USH1 cases revealed 23 MYO7A mutations in 20 families with cosegregation and absence in controls ([PMID:8900236]). USH1B accounts for ~75% of USH1 cases, with MYO7A variants identified in >189 probands across >20 families ([PMID:7870171]).
Overall ClinGen clinical validity: Definitive
Segregation analysis in 20 AR families confirms pathogenicity of truncating and missense alleles. Case reports and cohort studies describe >100 distinct MYO7A variants, including missense, nonsense, frameshift, and splice-site changes. A representative frameshift variant is c.2307del (p.Asn769fs), which truncates the motor domain and is homozygous in affected individuals ([PMID:23882135]).
ClinGen genetic evidence: Strong
Rationale: 23 unique MYO7A mutations in 20 USH1 families with autosomal recessive segregation and absence in 50 controls ([PMID:8900236]).
In vitro assays demonstrate that USH1B missense mutations impair actin-activated ATPase activity and reduce duty ratio of myosin VIIA, leading to loss of motor function ([PMID:18700726]). Mouse shaker-1 (Myo7a) mutants recapitulate auditory and retinal phenotypes, confirming the role of MYO7A in sensory cell function.
ClinGen functional evidence: Moderate
Rationale: Multiple biochemical studies show disrupted motor activity and actin binding in MYO7A variants, and animal models replicate human USH1B features.
No substantial conflicting reports disputing the MYO7A–Usher syndrome association have been published. Genetic and functional data are concordant across populations.
Biallelic loss-of-function and deleterious missense variants in MYO7A consistently cause Usher syndrome type 1B via haploinsufficiency or dominant-negative mechanisms. The strong genetic evidence, supported by functional impairment in vitro and in vivo models, establishes a definitive gene–disease relationship. Clinical genetic testing of MYO7A should be prioritized in patients with congenital deafness and early-onset retinitis pigmentosa.
Key Take-home: MYO7A genetic screening enables early diagnosis of Usher syndrome type 1B, guiding audiological intervention, vestibular management, and prospective gene therapy.
Gene–Disease AssociationDefinitiveMYO7A mutation identified in >189 USH1B probands across >20 families with extensive segregation (PMID:8900236; PMID:7870171) Genetic EvidenceStrong23 unique MYO7A mutations in 20 unrelated USH1 families with AR segregation (PMID:8900236) Functional EvidenceModerateMissense and truncating MYO7A variants disrupt motor function in vitro and replicate sensory defects in models (PMID:18700726) |