Moradi, P; (2014) Leber Congenital Amaurosis and other autosomal recessive retinal dystrophies: A clinical and molecular genetic study. Doctoral thesis , UCL (University College London).

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Abstract

Leber congenital amaurosis (LCA) and the early onset retinal dystrophies (EORD) are a spectrum of autosomal recessively inherited genetic conditions affecting children who have visual impairment starting under the age of five years. There are currently 19 known genes that account for approximately two thirds of cases. Only two of these 19 genes (IMPDH 1 and CRX; not studied in this project) have been found to cause autosomal dominant LCA. This genetic heterogeneity makes the identification of these causative genes expensive and time consuming. Phenotype-genotype correlations are therefore important in directing efforts to determine the molecular cause of disease. The aims of this research project were to recruit and clinically characterise a large panel of LCA and EORD patients and to identify the underlying genetic cause of autosomal recessive disease. Patients were recruited from Moorfields Eye Hospital and Great Ormond Street Hospital. A full clinical examination was carried out. DNA samples were analysed using the Asper Ophthalmics LCA microarray chip and by direct sequencing. Large families, with several affected members, were examined using the Affymetrix gene chip arrays for regions of homozygosity and candidate gene sequencing was performed. DNA samples from 158 patients were obtained and 117 patients were examined clinically. A definitive molecular diagnosis was obtained for 26% of patients. Of the cohort of 158 patients with one or two mutated alleles identified and genotyped: RPE65 accounts for 1% of this cohort, 6% are due to mutations in CRB1, 15% are due to RDH12 mutations and 11% are due to mutations in CEP290. Two families were identified with novel CRALBP mutations. The genotype yield from the period of this research, August 2006- August 2008, is lower than that expected with newer technologies in 2014; such as next generation sequencing (NGS) or whole exome sequencing. Useful prognostic information gained will help future patients with these disorders. Patients with a molecular diagnosis may be eligible for clinical trials of gene replacement therapy.

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