Abstract
Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.
Highlights
Usher syndrome (USH) is a group of autosomal recessively inherited disorders characterized by bilateral sensorineural hearing loss (SNHL) and a gradual retinal degeneration typified as retinitis pigmentosa (RP)
visual field (VF) was significantly constricted to tubular vision, and ERG was diminished in both rod and cone responses
Since the RP onset ages for the two patients were 15 and 13 years of age, both of which were in accordance with the typical clinical manifestations presented by Usher syndrome type 2, we concluded that the two patients from family USH01 displayed USH type 2 phenotypes
Summary
Usher syndrome (USH) is a group of autosomal recessively inherited disorders characterized by bilateral sensorineural hearing loss (SNHL) and a gradual retinal degeneration typified as retinitis pigmentosa (RP). Three major clinical subtypes have been described called USH type 1, type 2, and type 3 They are mainly distinguished by the severity and progression of the deafness and the presence of vestibular defects [6,7]. USH type 1, accounting for 30% to 40% of total USH, is the most severe clinical form typified by profound congenital deafness, early onset of visual impairment (usually within the first decade of life), and vestibular dysfunction [9]. Typical clinical manifestations include normal vestibular functions, and moderate to severe congenital hearing impairments rather than totally deafness. Patients with Usher type 3 are manifested by variable onset of progressive hearing loss, variable vestibular dysfunction, and variable onset of visual impairment [3]. Other than all above mentioned USH causative genes, the PDZD7 gene encodes a protein which would interact with proteins encoded by DFNB31
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