Genotype-phenotype correlations seen in a cohort of British patients with Leber’s congenital amaurosis

Abstract

Introduction: The purpose of this study was to investigate the relationship between genotype and phenotype in a large cohort of patients with Leber’s Congenital Amaurosis (LCA). A trial of gene therapy in a subset of patients with LCA due to mutations in the RPE65 gene is planned and it is essential that patients with mutations in this gene and others are identified and the phenotypes are carefully refined. Methods: Patients were recruited from two main centers (Moorfields Eye Hospital and Great Ormond Street Hospital, London, UK). Where possible, all patients underwent a full ophthalmic examination including refraction, Goldman visual fields, optical coherence tomography, fundus autofluorescence, and digital fundus photography. DNA aliquots were sent for analysis using the LCA chip (Asper Bio), which identifies previously published mutations in eight known genes. Direct sequencing of three genes, RPE65, RDH12 and CRB1, was carried out. Results: Eighty-six probands from 75 families were recruited. Phenotypic information was obtained in 70 subjects. A definitive molecular genetic diagnosis was obtained in 16/62 (26%) families: 9 patients were identified with mutations in RPE65; 2 in RPGRIP1, 2 in GUCY2D; 1 in AIPL1; and 9 with mutations in CRB1; no patients with LCA were found to have mutations in RDH12. There is a characteristic phenotype recognizable in both RPE65 and CRB1 patients. Conclusions: Identification of causative mutations remains a challenge but use of the LCA chip and careful assessment of the phenotype can improve the efficiency of genotyping strategies. RDH12 is not a cause of LCA in our cohort of patients.