![]() ![]() She had a history of reduced vision and hearing loss since childhood, and now undergoes annual ophthalmological evaluation. The proband was a 51-year-old female seen in our clinic following relocation from a different health board. In this study, we report a case carrying novel biallelic variants in USH2A causing progressive early adolescent onset visual and hearing impairment consistent with Usher Syndrome Type IIA. There is a high degree of allelic heterogeneity, with many of the causative variants being identified in single cases. Mutations in USH2A are reported to cause 30–40% of Usher Syndrome Type II cases and 10 –15% of recessive RP cases. The precise function of USH2A remains unclear, but may have a role in cell development and maintenance. Expression is restricted to the basement membrane of retinal photoreceptors and cochlear hair cells of the inner ear. Multiple isoforms exist, but the full-length protein product is a 5202 amino acid (aa) protein of 580 kDa. Homozygous or compound-heterozygous mutations in the gene encoding usherin ( USH2A) on chromosome 1q41 have been implicated in the pathogenesis of non-syndromic retinitis pigmentosa (RP, OMIM 613809) and in Usher Syndrome Type IIA (OMIM 276901) where RP occurs alongside hearing loss. The mode of inheritance is typically autosomal recessive. To date, causative mutations in multiple genes, including MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, GPR98, WHRN, and CLRN1 have been identified. In addition to clinical variability, there is extensive genetic heterogeneity underlying the condition. Usher Syndrome can be divided by clinical characteristics into 3 types by the age of onset and severity of deafness, imbalance and visual loss. Usher syndrome was first described in 1858 by Albrecht Von Graefe, but was given it’s eponymous name for Charles Usher, a Scottish eye doctor who identified and described the disorder’s hereditary nature and recessive inheritance pattern in 1914. Usher Syndrome is the commonest cause of combined inherited blindness and deafness with an estimated prevalence of 1 in 30,000. The identification of novel mutations in USH2A increases the spectrum of genetic variations that lead to Usher Syndrome, aiding genetic diagnosis, assessment of patient prognosis, and emphasising the importance of genetic testing to identify new mutations in patients with undiagnosed progressive visual loss. Comprehensive in silico analysis confirmed that these mutations are the probable cause of Usher Syndrome Type IIA in this individual. Segregation analysis confirmed that these variants were biallelic in the affected case. ![]() Genetic testing identified two novel USH2A variants, resulting in the premature termination codon p.Leu30Ter and a missense mutation p.Cys3251Tyr. Clinical and molecular genetic assessment of the proband was consistent with a diagnosis of Usher Syndrome Type IIA. She was registered partially sighted age 46. Now 52 years old, latest best corrected visual acuity (BCVA) stands at Logmar Right Eye (RE) 0.8 and Left Eye (LE) 0.2, with significantly constricted visual fields bilaterally. Our patient presented at age 13 with progressive visual field loss and hearing loss, associated with early onset of cataract in her 40s requiring lens extraction. We report a case carrying novel biallelic variants in USH2A causing progressive early adolescent onset visual and hearing impairment consistent with Usher Syndrome Type IIA. The condition is clinically and genetically heterogeneous, with no current treatment. ![]() Usher Syndrome is the commonest cause of inherited blindness and deafness. ![]()
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