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Title: Genetic analysis of two forms of inherited childhood blindness : foveal hypoplasia and Leber congenital amaurosis
Author: Al-Araimi, Musallam Said Mohammad
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Childhood blindness is a global public health problem with a worldwide prevalence of 0.75/1000 children. More than 1.5 million children are registered blind in the world. The work described in this thesis aims to identify the genetic basis, and so provide new insights into the clinical phenotype, of two recessively inherited disorders; Leber Hereditary Amaurosis (LCA) and FHONDA (Foveal Hypoplasia and Optic Nerve Decussation Abnormalities) syndrome. LCA is a severe inherited retinal dystrophy that presents at birth or within the first year of life. LCA is a genetically heterogeneous condition with over 20 genes identified to date. This thesis details the genetic analysis of ten "large LCA pedigrees leading to the identification of novel mutations in known LCA genes in six of the families. For each family, whole genome single nucleotide polymorphism genotyping was performed on pooled DNA from the affected members. Regions of homozygosity shared between the affected individuals within each family were identified and confirmed by microsatellite genotyping. Six of the families showed convincing regions of homozygosity over known LCA genes and sequencing of these led to the identification of six novel mutations, three in LCAS, two in GUCY20 and one in CEP290. FHONDA syndrome is a rare disorder that describes an underdeveloped fovea and optic nerve decussation defect without albinism. Occasionally mild anterior segment dysgenesis is also associated with this disorder. This thesis details the identification of the gene mutated in FHONDA syndrome. FHONDA syndrome had previously only been described in one consanguineous family of Pakistani origin and linkage analysis in this family allowed the causative gene to be mapped to a 6.S-Mb region on chromosome 16q22-24. In this thesis, a second consanguineous family from Afghanistan, with the same clinical phenotype, was identified and the mutated gene mapped to the same locus at chromosome 16q. High-resolution genotyping in both families refined the disease gene interval to 3-Mb containing 32 genes. Sequential screening of all the genes within this interval identified different homozygous mutations in SLC38AB in both families. Subsequent sequencing of this gene in additional patients identified another three different homozygous mutations. The identification of the disease causing genes in both LCA and FHONDA is important as it facilitates the genetic counselling of families, contributes to phenotype/genotype studies, extends the mutation spectrum for each gene which aids protein characterisation and ultimately identifies a cohort of patients for future therapeutic and early prevention strategies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available