title: Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe.
abstract: Variation in the ABCA4 locus has emerged as the most prevalent cause of monogenic retinal diseases. The study aimed to discover causative ABCA4 mutations in a large but not previously investigated cohort with ABCA4-related diseases originating from Central Europe and to refine the genetic relevance of all identified variants based on population evidence. Comprehensive clinical studies were performed to identify patients with Stargardt disease (STGD, n = 76) and cone-rod dystrophy (CRD, n = 16). Next-generation sequencing targeting ABCA4 was applied for a widespread screening of the gene. The results were analyzed in the context of exome data from a corresponding population (n = 594) and other large genomic databases. Our data disprove the pathogenic status of p.V552I and provide more evidence against a causal role of four further ABCA4 variants as drivers of the phenotype under a recessive paradigm. The study identifies 12 novel potentially pathogenic mutations (four of them recurrent) and a novel complex allele p.[(R152*; V2050L)]. In one third (31/92) of our cohort we detected the p.[(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Causative ABCA4 mutations account for 79% of STGD and 31% of CRD cases. A combination of p.[(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression. The comprehensive, population-specific study expands our knowledge on the genetic landscape of retinal diseases.
authors.affiliation: Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Ścieżyńska
authors.affiliation: Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw/Kajetany, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Oziębło
authors.affiliation: Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland; Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ambroziak
authors.affiliation: Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Korwin
authors.affiliation: Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Szulborski
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; Center for Medical Genetics GENESIS, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Krawczyński
authors.affiliation: Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw/Kajetany, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Stawiński
authors.affiliation: Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Szaflik
authors.affiliation: Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jacek P
authors.initials: JP
authors.lastname: Szaflik
authors.affiliation: Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland. Electronic address: rploski@wp.pl.
authors.forename: Rafał
authors.initials: R
authors.lastname: Płoski
authors.affiliation: Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland; Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw/Kajetany, Poland. Electronic address: m.oldak@ifps.org.pl.
authors.forename: Monika
authors.initials: M
authors.lastname: Ołdak
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000483:Alleles; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015995:Prevalence; D058499:Retinal Dystrophies / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA
keywords: ABCA4; Complex allele; Cone-rod dystrophy; Mutation; Next-generation sequencing; Stargardt disease