Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes.
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.
Coppieters
Frauke
F
Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
Casteels
Ingele
I
Meire
Françoise
F
De Jaegere
Sarah
S
Hooghe
Sally
S
van Regemorter
Nicole
N
Van Esch
Hilde
H
Matuleviciene
Ausra
A
Nunes
Luis
L
Meersschaut
Valérie
V
Walraedt
Sophie
S
Standaert
Lieve
L
Coucke
Paul
P
Hoeben
Heidi
H
Kroes
Hester Y
HY
Vande Walle
Johan
J
de Ravel
Thomy
T
Leroy
Bart P
BP
De Baere
Elfride
E
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
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