title: In Silico Functional Meta-Analysis of 5,962 ABCA4 Variants in 3,928 Retinal Dystrophy Cases.
abstract: Variants in the ABCA4 gene are associated with a spectrum of inherited retinal diseases (IRDs), most prominently with autosomal recessive (ar) Stargardt disease (STGD1) and ar cone-rod dystrophy. The clinical outcome to a large degree depends on the severity of the variants. To provide an accurate prognosis and to select patients for novel treatments, functional significance assessment of nontruncating ABCA4 variants is important. We collected all published ABCA4 variants from 3,928 retinal dystrophy cases in a Leiden Open Variation Database, and compared their frequency in 3,270 Caucasian IRD cases with 33,370 non-Finnish European control individuals. Next to the presence of 270 protein-truncating variants, 191 nontruncating variants were significantly enriched in the patient cohort. Furthermore, 30 variants were deemed benign. Assessing the homozygous occurrence of frequent variants in IRD cases based on the allele frequencies in control individuals confirmed the mild nature of the p.[Gly863Ala, Gly863del] variant and identified three additional mild variants (p.(Ala1038Val), c.5714+5G>A, and p.(Arg2030Gln)). The p.(Gly1961Glu) variant was predicted to act as a mild variant in most cases. Based on these data, in silico analyses, and American College of Medical Genetics and Genomics guidelines, we provide pathogenicity classifications on a five-tier scale from benign to pathogenic for all variants in the ABCA4-LOVD database.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Stéphanie S
authors.initials: SS
authors.lastname: Cornelis
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Bax
authors.affiliation: Department of Ophthalmology, Columbia University, New York, New York.
authors.forename: Jana
authors.initials: J
authors.lastname: Zernant
authors.affiliation: Department of Ophthalmology, Columbia University, New York, New York.|Department of Pathology & Cell Biology, Columbia University, New York, New York.
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.affiliation: Department of Public Health, K.G. Jebsen Center for Genetic Epidemiology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Lars G
authors.initials: LG
authors.lastname: Fritsche
authors.affiliation: Departments of Clinical Genetics and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
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, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D003198:Computer Simulation; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype; D058499:Retinal Dystrophies / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters
keywords: ABCA4; genotype-phenotype correlation; in silico prediction; meta-analysis; mild variants; retinal dystrophy