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Investigation of the genetic cause and related phenotypes of rare early onset retinal dystrophies

Hull, S; (2016) Investigation of the genetic cause and related phenotypes of rare early onset retinal dystrophies. Doctoral thesis , UCL (University College London). Green open access

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Early onset retinal dystrophies (EORD) are a group of disorders presenting in childhood with degenerative abnormalities in photoreceptor cells. They are one of the leading causes of sight impairment in the United Kingdom. Since the initial discovery of Rho causing dominant retinitis pigmentosa in 1990, more than 160 genes have been associated with retinal dystrophy. Many, including CRB1, CRX, and RPE65 exhibit phenotypic heterogeneity and have been associated with more than one retinal disorder. Increasingly, with the advent of next generation sequencing, the association of non-syndromic retinal dystrophy with mutations in syndromic genes has been reported including CEP290, CLN3, and BBS1. In this thesis, a large cohort of patients with EORD underwent both detailed phenotyping to characterise their condition and molecular genetic investigations to identify and investigate the underlying causative variants. Many areas of the presented research were driven by novel findings on whole-exome sequencing such as the association of IFT140 with non-syndromic retinal dystrophy or CRX with macular dystrophy. Other areas were driven by unusual groups of patients with limited published data on their condition such as COL18A1 and Knobloch syndrome, with novel phenotypic features of cone-rod dysfunction and pigmentary glaucoma. Sanger sequencing was performed for confirmation and segregation of identified variants but in addition, for investigation of phenotypically similar patient panels for unusual gene associations. This included systemically mild Hermansky-Pudlak syndrome due to HPS6, juvenile macular dystrophy and CDH3, macular dystrophy and CRX and microcephaly with familial exudative vitreoretinopathy due to LRP5. Functional investigation of missense variants in IFT140 related retinal dystrophy was performed with transient cell transfection. This thesis highlights the vast heterogeneity of rare forms of EORD, presents novel clinical and molecular data and describes the key features of conditions to aid diagnosis and opportunities for future research.

Type: Thesis (Doctoral)
Title: Investigation of the genetic cause and related phenotypes of rare early onset retinal dystrophies
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Retinal dystrophy, Phenotype, Genotype
URI: http://discovery.ucl.ac.uk/id/eprint/1476996
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