title: Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.
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.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.forename: Ingele
authors.initials: I
authors.lastname: Casteels
authors.forename: Françoise
authors.initials: F
authors.lastname: Meire
authors.forename: Sarah
authors.initials: S
authors.lastname: De Jaegere
authors.forename: Sally
authors.initials: S
authors.lastname: Hooghe
authors.forename: Nicole
authors.initials: N
authors.lastname: van Regemorter
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Ausra
authors.initials: A
authors.lastname: Matuleviciene
authors.forename: Luis
authors.initials: L
authors.lastname: Nunes
authors.forename: Valérie
authors.initials: V
authors.lastname: Meersschaut
authors.forename: Sophie
authors.initials: S
authors.lastname: Walraedt
authors.forename: Lieve
authors.initials: L
authors.lastname: Standaert
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Heidi
authors.initials: H
authors.lastname: Hoeben
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Walle
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D001530:Belgium; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis / Q000379:methods; D020869:Gene Expression Profiling; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics; D058499:Retinal Dystrophies / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D011506:Proteins