Abstract
PurposeTo present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease.MethodsRetrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK).ResultsThe mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented.ConclusionsThe reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.
Highlights
Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) are genetically and phenotypically heterogeneous groups of inherited retinal diseases, with widely overlapping features
The first FDAand EMA-approved gene therapy is available for LCA/ EOSRD-associated with RPE65 [9, 10], and there are multiple other trials underway for LCA/EOSRD and other inherited retinal diseases
We describe the detailed retinal phenotype of five cases, from four unrelated families, with LCA/ EOSRD harboring disease-causing sequence variants in genes not usually associated with the disease
Summary
Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) are genetically and phenotypically heterogeneous groups of inherited retinal diseases, with widely overlapping features. The first FDAand EMA-approved gene therapy is available for LCA/ EOSRD-associated with RPE65 [9, 10], and there are multiple other trials underway for LCA/EOSRD and other inherited retinal diseases. It is of paramount importance to molecularly characterize LCA/ EOSRD patients, in order to facilitate access to, and potential benefit from, the on-going advances in the field. We describe the detailed retinal phenotype of five cases, from four unrelated families, with LCA/ EOSRD harboring disease-causing sequence variants in genes not usually associated with the disease. We thereby extend the phenotypic spectrum associated with PRPF8, PRPH2, RP1, and RPGR, and the genotypic spectrum of LCA/EOSRD
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