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

Frauke Coppieters (1) , Ingele Casteels (2) , Françoise Meire (3) , Sarah de Jaegere (1) , Sally Hooghe (1) , Nicole van Regemorter (4) , Hilde van Esch (5) , Aušra Matulevičienė (6) , Luis Nunes (7) , Valérie Meersschaut (8) , Sophie Walraedt (9) , Lieve Standaert (10) , Paul Coucke (11) , Heidi Hoeben (12) , Hester y Kroes (13) , Johan Vande Walle (14) , Thomy de Ravel , Bart P. Leroy (9) , Elfride Bw de Baere (1)

1 Center for Medical Genetics [Ghent]
2 Department of Ophthalmology
3 Ophthalmology
4 Centre de Génétique de Bruxelles
5 Centre for Human Genetics
6 Department of Human and Medical Genetics
7 Eye Genetics Research Group
8 Department of Radiology
9 Department of Ophthalmology
10 Revalidation Center Spermalie
11 Dpt. Medical Genetics - Head Collagen Lab
12 Department of Nephrology
13 Department of Biomedical Genetics
14 Department of Pediatrics

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophies, 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, AIPL1 and 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.

Mots clés: Life Sciences

Frauke Coppieters, Ingele Casteels, Françoise Meire, Sarah de Jaegere, Sally Hooghe, et al.. Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Human Mutation, 2010, 31 (10), ⟨10.1002/humu.21336⟩. ⟨hal-00613751⟩