Clinical Variability in CEP290-Related LCA and Identification of Potential Modifier Alleles in AHI1

Abstract

Purpose: : Leber Congenital amaurosis (LCA) is one of the ciliopathies, an emerging group of diseases characterized by mutations in genes encoding ciliary proteins. CEP290 mutations are a major cause of LCA, but are also associated with the more severe Joubert syndrome (JS), Senior-Loken syndrome (SLS) and lethal Meckel-Grüber syndrome. It is presumed that modifiers may play a important role in the pathogenesis of this broad spectrum of phenotypes caused by CEP290 mutations.

Methods: : A cohort of 91 LCA patients mainly of Belgian origin underwent LCA chip analysis and subsequent direct sequencing of 6 well-established genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1 and CRX). In addition, 12 patients with SLS or LCA-JS were sequenced for CEP290. The overall phenotype of all patients with an established molecular diagnosis was studied in detail. The AHI1 gene was sequenced in 9 patients with CEP290-related LCA and mental retardation (MR) as a candidate modifier gene.

Results: : Our approach revealed mutations in 71% of the LCA cohort, with major contribution of CEP290 (30%). Exhaustive re-inspection of the overall phenotype of CEP290-related LCA identified novel insights into the course of retinal disease and associated clinical manifestations. Interestingly, screening of the AHI1 gene revealed a novel AHI1 mutation, p.Asn811Lys, in the most severely affected patient out of three patients with the same CEP290 genotype but different neurological involvement. Moreover, a second novel missense variant, p.His758Pro, was identified in another LCA-patient with MR. These two AHI1 mutations might thus represent modifiers of neurological involvement of CEP290-related disease.

Conclusions: : This study identified CEP290 as the major causal disease gene for LCA in the Belgian population. A CEP290-related retinal phenotype and its clinical course were well established for the first time in a larger patient group with LCA. The identification of potential modifiers of CEP290-related disease might importantly contribute to a refined prognosis based on a molecular diagnosis.

Keywords: gene modifiers • ciliary processes • retinal degenerations: hereditary