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Usher syndrome type 1 is an autosomal recessive disorder characterized by congenital profound sensorineural hearing loss, vestibular areflexia, and prepubertal retinitis pigmentosa. Pathogenic variants in the myosin VIIA gene (MYO7A) underlie the USH1B locus, accounting for a substantial proportion of USH1 cases (MYO7A, Usher syndrome type 1). Early genetic testing enables diagnosis before visual symptoms emerge, informing timely interventions.
Multiple case reports across diverse populations have identified biallelic MYO7A variants in USH1 patients. A Japanese cohort study found a nonsense mutation c.52C>T (p.Gln18Ter) in a 6-year-old boy with pre-symptomatic retinitis pigmentosa (PMID:23237960). Compound heterozygous missense and splice-site variants (c.3742G>A (p.Glu1248Lys) and c.6051+1G>A) were cosegregated in two Chinese siblings with severe hearing loss and early retinitis pigmentosa (PMID:23559863). A novel frameshift c.3848_3851dup (p.Asn1285LeufsTer24) in exon 30 and c.2239_2240delAG (p.Arg747SerfsTer16) in exon 19 were reported in another Chinese family, expanding the mutational spectrum (PMID:28688563).
Large-scale studies confirm the high frequency and segregation of MYO7A variants. In 227 Japanese non-syndromic deaf children, recessive MYO7A mutations were detected in ~1.3–2.2% of cases, implicating late-onset walking as a clinical clue to USH1 (PMID:26791358). A retrospective French cohort of 53 biallelic MYO7A patients detailed a consistent rod–cone dystrophy with linear decline in visual function and variable retinal structural changes (PMID:31479088). Segregation analyses in consanguineous families revealed two affected siblings sharing novel splice-site mutations c.5648G>A (p.Arg1883Gln) and c.6238-1G>C, absent in 100 controls (PMID:36484953).
The variant spectrum includes >50 distinct alleles: nonsense (e.g., c.52C>T (p.Gln18Ter)), frameshift (e.g., c.2241_2242del (p.Arg747SerfsTer16)), splice-site (e.g., c.6051+1G>A), and missense changes affecting motor and binding domains. Recurrent alleles such as p.Arg212His and p.Gly25Arg were noted in multiple families, suggesting potential population-specific founders in certain cohorts (PMID:8900236). Carrier frequencies remain low (<1%), consistent with AR inheritance.
Functional assays demonstrate that USH1B-associated MYO7A mutations abolish or reduce actin-activated ATPase activity, impair duty ratio, and disrupt melanosome transport in retinal pigment epithelium models. Mutations such as p.Gly25Arg, p.Arg212Cys, p.Ala397Asp, and p.Glu450Gln eliminate motor function, while p.Pro503Leu decreases actin affinity (PMID:18700726). In vivo studies in mouse models recapitulate deafness and retinal degeneration, underscoring haploinsufficiency as the pathogenic mechanism.
Integration of robust genetic segregation, recurrent and private pathogenic variants, and concordant functional data across multiple populations establishes MYO7A as definitively associated with USH1. Early genetic diagnosis facilitates audiological and ophthalmological surveillance, informs genetic counseling, and enables future gene augmentation or editing therapies. Key Take-home: MYO7A variant analysis is essential for early and accurate diagnosis of Usher syndrome type 1, guiding clinical management and emerging therapeutics.
Gene–Disease AssociationDefinitiveOver 20 families worldwide with biallelic MYO7A variants, segregation across consanguineous and multiplex pedigrees, and multi-population case series showing consistent phenotype Genetic EvidenceStrongMultiple unrelated probands (n>10) with biallelic LoF and missense variants segregating in families (PMID:23237960; PMID:23559863) Functional EvidenceModerateIn vitro motor function assays demonstrate actin-activated ATPase impairment and animal studies confirm phenotype (PMID:18700726; PMID:8900236) |