title: Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark.
abstract: Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in ~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
authors.forename: Galuh D N
authors.initials: GD
authors.lastname: Astuti
authors.affiliation: Kennedy Center Eye Clinic, Glostrup Hospital, Glostrup, Denmark.|Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Bertelsen
authors.affiliation: Department of Ophthalmology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Markus N
authors.initials: MN
authors.lastname: Preising
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.affiliation: Department of Ophthalmology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.affiliation: Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
authors.forename: Sultana M H
authors.initials: SM
authors.lastname: Faradz
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Al-Nafees Medical College and Hospital, Isra University, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: Kennedy Center Eye Clinic, Glostrup Hospital, Glostrup, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D000328:Adult; D002648:Child; D003718:Denmark; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D059645:Mutation Rate; D020125:Mutation, Missense; D010375:Pedigree; D012326:RNA Splicing; D019745:cis-trans-Isomerases / Q000235:genetics*; D000099178:Retinoid Isomerohydrolase
chemical_list: D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase