Defining the clinical and molecular spectrum of inherited eye diseases in community settings

Abstract

Inherited eye diseases are an important contributor to the burden of childhood blindness globally. These conditions are often associated with significant phenotypic and genetic heterogeneity and are extremely difficult to study in a general population setting. This thesis details the study of inherited eye diseases in genetically isolated populations including the North American Amish and rural Pakistani and Palestinian communities. Here, an enrichment of disease-causing founder mutations arising from common ancestry, characteristic marriage patterns and geographical isolation, combined with the often large family sizes typical of families in these regions, enables powerful genomic studies to identify pathogenic sequence variants. As well as providing an important opportunity to learn about the genetic causes of inherited eye diseases, these studies also provide desperately required healthcare benefits for the families and populations involved. Chapter 3 describes studies of oculocutaneous albinism (OCA) in 40 Amish and Pakistani families. Results from comprehensive clinical, genomic and functional studies, initiated by a search for the cause of OCA in a number of Amish families, provide strong evidence for the pathogenicity of two common TYR gene variants [p.(Ser192Tyr) and p.(Arg402Gln)] when inherited in cis. These variants were previously considered gene polymorphisms although this has been heavily debated in many studies, and these variants are currently variably reported and even potentially excluded by clinical testing laboratories. The findings reported in this thesis have important diagnostic implications by helping clarify the contribution of these variants to the OCA phenotype, and by promoting the reporting the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele. This will likely increase the molecular diagnoses in albinism patients with missing heritability by 25-50%. This chapter also entails a comprehensive investigation involving genetic studies alongside an exhaustive literature review of all published OCA genetic causes in Pakistani families, including cross-referencing with established genomic databases to evidence the likely causality of each gene variant. Chapter 4 entails clinical and genomic findings in four families with phenotypic features highly suggestive of a ciliopathy disorder. Findings include identification of novel SCAPER and BBS5 variants, enabling a more precise definition of the SCAPER clinical phenotype. This work also consolidates an INPP5E c.1879C>T; p.(Gln627*) variant, a likely pathogenic founder alteration present in Northern Pakistan, as a cause of MORM syndrome. Chapter 5 documents studies of families with rare and ultra-rare inherited ocular diseases in Pakistani and Palestinian communities. This includes consolidating SDHD dysfunction as a cause of mitochondrial disease through investigations of an extended Palestinian family, facilitating a clearer delineation of the variable ocular (and non-ocular) phenotypical features. Alongside this, the identification of novel and known variants in ALDH1A3, FYCO1, TDRD7, CYP1B1, ATOH7, LRP5, FRMD7 and HPS1 in Pakistani communities contributes to an improved knowledge of the genetic spectrum and frequencies of various forms of inherited eye diseases regionally. The comprehensive OCA and BBS datasets provide notably improved knowledge, as well as a centralised repository, of the genetic spectrum and regional frequencies of the molecular causes of these conditions in the Amish and in Pakistan. Ultimately, these findings will greatly facilitate the establishment of robust cost-effective accurate diagnostic genetic testing, clinical management and counselling efforts. Together the work of this thesis describes data of scientific importance, and highlights the immense value of translational community research studies to deliver clinical benefits locally and globally in the field of inherited eye diseases.