Saihan, Z.; (2012) Clinical and molecular genetics of Usher syndrome. Doctoral thesis , UCL (University College London).

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Abstract

Usher syndrome (USH) is the name given to a group of recessively inherited disorders characterised by hearing loss, progressive visual loss due to a retinal degeneration termed retinitis pigmentosa (RP) and in some cases vestibular dysfunction. It is the most common form of syndromic RP and is clinically and genetically heterogeneous. There are three clinical subtypes termed USH1, USH2 and USH3, which are defined by the severity of hearing loss and vestibular dysfunction with visual loss due to RP being common to each subtype. To date, mutations in nine genes have been associated with the three clinical subtypes of Usher syndrome as well as non-syndromic hearing loss and RP. This wide spectrum of clinical and genetic variability provides challenges to clinicians in making a diagnosis of Usher syndrome and delivering prognostic information to affected individuals, whilst the genetic heterogeneity presents problems to geneticists attempting to achieve a molecular diagnosis. This study aims to address these issues by determining the distribution of clinical and molecular subtypes of USH in the United Kingdom (UK). This study represents an original contribution to the knowledge of Usher syndrome, as it is the first prospective clinical study to sequence the coding regions of each of the nine genes associated with this disorder in 187 affected families regardless of their clinical subtype. Detailed ophthalmic phenotyping was performed in 219 individuals. This comprehensive strategy of molecular analysis afforded the opportunity to interrogate for the possibility of digenic effects for which no evidence was found. This strategy enabled the discovery of an atypical and novel phenotype associated with the USH1C gene. A molecular diagnosis was achieved in 80% of families with Usher syndrome and the ophthalmic phenotype of a large cohort of affected individuals with Usher syndrome has been further delineated. This study has resulted in a large cohort of UK patients with a confirmed molecular diagnosis and detailed ophthalmic phenotyping, which will provide a framework for subsequent longitudinal studies enabling the characterisation of how visual function progresses over time. Understanding the natural history of this disorder in genotyped individuals will help pave the way for subsequent gene-directed therapy studies in the future.

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