CEP290 mutation spectrum and delineation of the associated phenotype in a large German cohort: a monocentric study.

Abstract

PURPOSE\nGene therapy for Leber congenital amaurosis (LCA) is becoming available, therefore, it is crucial to identify eligible candidates. We report the spectrum and associated phenotype of CEP290 mutations in the largest German cohort observed by a single clinical site.\n\n\nDESIGN\nprospective cohort study METHODS: Twenty-three patients with mutations in CEP290 were included. Genomic DNA was analyzed by Sanger sequencing or high-throughput sequencing for all RP-associated genes in patients, segregation analysis was done in family members. Patients underwent functional and morphological examinations including fundus autofluorescence and SD-OCT.\n\n\nRESULTS\nThe most frequent mutation was c.2991+1655A>G, found in 87% of patients (20/23). Thirty percent of patients (7/23) carried the mutation in apparent homozygous state and 57% (13/23) in likely compound heterozygous state. The most common clinical diagnosis was LCA and/or early onset severe retinal dystrophy in 82% (19/23), followed by retinitis pigmentosa in 14% (3/23) and cone-rod dystrophy (4%, 1/23). Best-corrected visual acuity (BVCA) was severely reduced to residual light perception and hand motion vision, exceptions were 3 patients with BCVA of 0.8 (Snellen). Visual field was severely decreased and electroretinogram was undetectable in most cases, however, retinal layers at the fovea appeared to be relatively well preserved. Systemic disorders were not noticed.\n\n\nCONCLUSIONS\nc.2991+1655A>G is by far the most important CEP290 mutation, contributing to 87% of CEP290 patients in Germany. In our cohort, a homozygous c.2991+1655A>G genotype presented with a more severe phenotype. National studies and further detailed phenotype analysis seem to be important to assess the need for and promise of specific gene therapies.