The Importance of the CEP290 (NPHP6) Gene in First-Pass Mutation Screening of Patients With Leber Congenital Amaurosis

Abstract

Purpose:: Recently the CEP290 (NPHP6) gene was identified as a novel gene for Leber congenital amaurosis (LCA), representing one of the most frequent causes of LCA. The major objective of this study was to determine the proportion of CEP290 mutations in a cohort of 69 north-western European LCA patients (mainly of Belgian origin), in whom a first-pass mutation screening was negative for mutations in known LCA genes.

Methods:: Sequencing of CEP290 mutation c.2991+1655A>G in 69 LCA patients in whom LCA chip analysis was negative (Asper Ophthalmics, version April 2004-August 2006). The clinical detection rate of the LCA chip was approximately 35% in our population. Upon the identification of thespecific CEP290 mutation in heterozygous state, all 53 coding exons of CEP290 were screened by direct sequencing to identify the mutation on the second allele.

Results:: Targeted mutation analysis of CEP290 mutation c.2991+1655A>G in our cohort of LCA patients revealed this mutation in 17/69 (24,6%) of the cases. In one patient this mutation was found in a homozygous state. In the other 16 cases this mutation occurred heterozygously. A second mutation was identified in 14/16 cases. Screening of the remaining two is ongoing. These findings demonstrate that the CEP290 gene is a major LCA gene in our population, in agreement with previous findings.

Conclusions:: The recurrent CEP290 mutation c.2991+1655A>G is found in 24,6% of a pre-screened mutation-negative LCA cohort. This mutation therefore is found in 17/110 (15.5%) of patients from the entire LCA patient cohort. Our study demonstrates the importance of including targeted CEP290 mutation analysis into first-pass mutation screening of LCA in order to significantly increase the clinical mutation detection rate.

Keywords: gene screening • retinal degenerations: hereditary • genetics