Molecular investigation of a large UK cohort of early onset retinal dystrophy

Abstract

Purpose: To molecularly investigate a consecutive series of 458 patients (382 famlies) with early-onset severe retinal dystrophy (EOSRD), including Leber Congenital Amaurosis, and to perform in-depth phenotyping to determine key clinical and molecular characteristics and relationships.

Methods: Consecutive patients from two tertiary referral centres with a clinical diagnosis of EOSRD (onset less than 5 years of age) were recruited. Molecular investigations included candidate gene Sanger sequencing, arrayed primer extension (APEX), next generation sequencing (NGS) with a 105 retinal gene panel, and whole exome-analysis. Clinical investigations included retinal imaging and electrophysiology.

Results: Analysis has so far identified likely disease-causing variants in 197 families. Mutations in 38 genes have been idenitifed with the 5 most frequent being CRB1 (18%, n=35), RDH12 (14%, n=28), RPE65 (12%, n=24) CEP290 (10%, n=20) and GUCY2D (5%, n=9). Considering the 185 unsolved families, no molecular diagnosis was apparent despite whole exome sequencing in 16, NGS retinal panel screening in 2 and APEX in the remaining 167. These 185 families are the subject of further investigation using whole exome and whole genome sequencing.<br /> <br /> Phenotype-genotype correlations that were identified included nummular retinal pigmentation with macular thickening and loss of lamination in CRB1 related dystrophy; photoattraction, peripheral fine white retinal dots, and absent/markedly reduced autofluorescence in RPE65 disease; and relatively normal fundus appearances in both CEP290 and GUCY2D associated disease.<br /> <br /> Non syndromic manifestations of genes previously reported to have systemic manifestations were also observed. This included IFT140 related retinal dystrophy in a family with no skeletal or renal manifestations of IFT140 related Mainzer-Saldino syndrome and COL18A1 related retinal dystrophy in a patient with normal neuroradiological imaging, unexpected for Knobloch syndrome.

Conclusions: The 5 most frequent molecular causes of EORD in this large cohort account for 59% of the genetically characterised families. Recognising key clinical features can help target molecular investigation but in atypical phenotypic presentations molecular diagnosis may only be achieved by NGS or whole-exome analysis. Early molecular diagnosis facilitates genetic counselling,including prognosis and is an essential prerequisite for gene-specific interventions.