A genotype-phenotype study of childhood onset retinal dystrophies

• Main Author: Dev Borman, Arundhati
• Other Authors: Moore, A. T. ; Webster, A. R.
• Published: University College London (University of London) 2016
• Subjects: 617.7
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.746122

Introduction The childhood onset retinal dystrophies comprise a clinically and molecularly heterogeneous group of disorders. To date, sixteen genes have been implicated in the pathogenesis of the spectrum of disorders comprising Leber Congenital Amaurosis (LCA) and Early Onset Retinal Dystrophy (EORD), accounting for approximately 70% of cases. Although a wide range of phenotypes have been observed within this spectrum, some genotype – phenotype associations are reported. Further detailed genotype – phenotype studies will be important for expanding our understanding of the effects of mutations in these genes on patients and their families. Our knowledge of the phenotypic effects of mutations in other genes implicated in childhood onset retinal dystrophies, such as the bestrophinopathies, continues to expand. Purpose To undertake detailed phenotypic studies into subjects with molecularly identified childhood onset retinal dystrophies, and to describe novel phenotypes. Methods Affected subjects and their families were recruited from Moorfields Eye Hospital to an ongoing Study into childhood onset retinal dystrophies. Subjects were examined clinically and those that were historically recruited to the Study were invited back for further phenotypic analyses, if their molecular cause was identified. Genetic analysis was performed using a variety of methods including DNA microarray analysis, autozygosity mapping, direct sequencing and whole exome sequencing. Results Between August 2008 and August 2011, 201 subjects from 186 families were recruited into the Childhood Onset Retinal Dystrophy Study, and categorised into 2 cohorts: cohort 1 - the generalised retinal dystrophies, comprising 177 subjects (166 families); and cohort 2 – subjects with a macular phenotype, comprising 24 subjects (20 families). The molecular cause was identified in 34.5% of subjects in cohort 1 and 25% of subjects in cohort 2. RDH12 accounted for 28% of mutations in cohort 1, 18% had mutations in CEP290, and 13% had mutations in RPE65. The subjects in cohort 2 with autosomal recessive bestrophinopathy all had bi-allelic mutations in BEST1. The phenotype associated with the different genes identified was expanded, and focused on those genes with limited reports of the phenotype, such as SPATA7, LRAT, RGR and BEST1. The phenotype associated with a gene not previously identified in human EORD, TUB, was studied, and the features associated with a novel macular phenotype named Benign Yellow Dot Dystrophy were characterised. Conclusions This study has expanded and refined our understanding of the phenotypes associated with mutations in genes that cause childhood onset retinal dystrophies, and has identified a novel phenotype. This work will allow accurate prognostic and genetic counselling to affected families, and provides phenotypic information that will be important in ascertaining disorders that may be suitable for clinical trials of novel therapies.