Chandra, A; (2014) The genetic associations of rhegmatogenous retinal detachment and ectopia lentis. Doctoral thesis , UCL (University College London).

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Abstract

A genetic predisposition to Rhegmatogenous Retinal Detachment (RD) has been suggested for over 40 years. Ectopia Lentis (EL) is known to have a genetic aetiology as part of Marfan Syndrome, other ocular syndromes and when occurring in isolation. This work investigates the genetic aetiology to these conditions in Mendelian and non Mendelian inheritance. The work in this thesis establishes a clear genotype-phenotype correlation between isolated EL and its most important causative gene: ADAMTSL4. This suggests that mutations in this gene result in a more severe phenotype than other genes causing EL. In doing so, a novel clinical grading system for this condition has also been developed. The expression of ADAMTSL4 and distribution of its protein within ocular tissue has also been investigated and suggests further roles for this protein in ocular development. Modelling of the protein was undertaken and provides insights for future investigations. Traditional and novel next generation investigative tools have also been employed to examine families with Mendelian inherited phenotypes including RD and EL. The role of a deleted exon in ADAMTS17 has been identified as playing a role in Weill-Marchesani Like syndrome. A novel ocular phenotype has also been defined in three families demonstrated to be caused by mutations in ADAMTS1 8. This gene has previously been described in few probands with ophthalmic phenotypes, and this work has further delineated the role of this gene. It is becoming clear that members of the ADAMTS family of proteins play a significant role in ocular development. Finally, over 1300 probands with non-Mendelian RD were recruited and closely phenotyped as part of this work. It has demonstrated novel racial differences in the phenotypes of those affected. This cohort contributed significantly towards the first genome wide association study (GWAS) into RD; and established for the first time the genetic contribution to this condition. Further funding has now been acquired to investigate this cohort further using a novel exome array. Preliminary quality control analysis has been performed; allowing a platform for further detailed analysis to identify putative functional variants associated with RD.

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