Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes

Frauke Coppieters,Françoise Meire,Elfride De Baere,Paul Coucke,Heidi Hoeben,Bart P Leroy,Johan Vande Walle,Nicole Van Regemorter,Hester Y Kroes,Hilde Van Esch,Thomy De Ravel,Sophie Walraedt,Valérie Meersschaut,Sally Hooghe,Sarah De Jaegere,Ingele Casteels,Luis Nunes,Lieve Standaert,Aušra Matulevičienė

doi:10.1002/humu.21336

Abstract

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease. © 2010 Wiley-Liss, Inc.

Highlights

Leber Congenital Amaurosis (LCA; MIM# 204000) was first described as a congenital type of retinitis pigmentosa (RP)
Several of them are implicated in other retinal dystrophies: CRB1, RPE65, RDH12 and SPATA7 are associated with both LCA and early-onset retinal dystrophy (EORD), which often overlap (Gu et al, 1997; den Hollander et al, 1999; Janecke et al, 2004; Wang et al, 2009)
Homozygous and compound heterozygous variants in one gene were each found in 13 patients; a single heterozygous variant was identified in 17 individuals

Summary

Introduction

Leber Congenital Amaurosis (LCA; MIM# 204000) was first described as a congenital type of retinitis pigmentosa (RP). One locus - LCA9 (Keen et al, 2003) - and the following 14 genes have been identified: GUCY2D (Perrault et al, 1996), RPE65 (Marlhens et al, 1997), CRX (Freund et al, 1998), AIPL1 (Sohocki et al, 2000a), RPGRIP1 (Dryja et al, 2001), CRB1 (den Hollander et al, 2001), RDH12 (Perrault et al, 2004), IMPDH1 (Bowne et al, 2006), CEP290 (den Hollander et al, 2006), RD3 (Friedman et al, 2006), LCA5 (den Hollander et al, 2007) and SPATA7 (Wang et al, 2009), with the involvement of TULP1 (Hagstrom et al, 1998) and LRAT (Thompson et al, 2001) under debate. Several of them are implicated in other retinal dystrophies: CRB1, RPE65, RDH12 and SPATA7 are associated with both LCA and early-onset retinal dystrophy (EORD), which often overlap (Gu et al, 1997; den Hollander et al, 1999; Janecke et al, 2004; Wang et al, 2009)

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Conclusion