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Title: Understanding the genetics of ocular coloboma and optic fissure closure
Author: Patel, Aara Bimal
ISNI:       0000 0004 7660 0360
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Ocular coloboma is a congenital eye defect consists of a ventrally located notch or gap in structures of the eye, including the iris, choroid, retina, and optic nerve and can cause complete blindness. It results from the failure of optic fissure closure during early eye morphogenesis. It is related to Microphthalmia (small eyes) and Anophthalmia (absence of eyes) forming the MAC spectrum of phenotypes. The genetic pathways underlying optic fissure closure are not completely understood and genetic diagnoses are rare. This thesis aims to elucidate the genetic pathways regulating fissure closure and identify candidate disease genes and potentially improve the rate of genetic diagnosis. To achieve these aims a combination of human molecular genetics, transcriptomics and ultrastructural analysis of the closing fissure was used. 98 individuals with MAC were screened on the Oculome, a targeted panel of 429 congenital eye disease genes. Disease-causing variants were identified in 8 individuals. Laser capture microdissection and transcriptome analysis identified novel sets of genes dynamically regulated in the closing human and mouse fissure margins. Bioinformatics analysis of these genes identified signalling pathways related to epithelial-to-mesenchymal transition, consistent with changes in cell morphology observed using electron microscopy. These 202 novel genes were assembled into a virtual optic fissure transcriptome panel. Exome sequencing of 16 individuals not solved using the Oculome panel, and 74 additional unsolved individuals with coloboma, and analysis with the help of this panel identified a small number of novel high impact variants of uncertain pathogenic significance in genes expressed at the fissure. This thesis showed that a small proportion of individuals with coloboma could be explained by mutations in known disease genes. It identified a new panel of candidate disease genes expressed at the human optic fissure. Based on the synthesis of ultrastructural and transcriptomic analyses it proposed a cellular mechanism of closure involving a transient epithelial to mesenchymal-like change in cell state and identified conserved, regulatory pathways involved in the process.
Supervisor: Sowden, J. C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available