title: Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant.
abstract: Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the "missing" variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Bax
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sangermano
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.forename: Alberta A H J
authors.initials: AA
authors.lastname: Thiadens
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Milan
authors.initials: M
authors.lastname: Phan
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.forename: Carla
authors.initials: C
authors.lastname: Westeneng-van Haaften
authors.forename: Terry A
authors.initials: TA
authors.lastname: Braun
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld-Vrieling
authors.forename: Ilse
authors.initials: I
authors.lastname: de Wijs
authors.forename: Merve
authors.initials: M
authors.lastname: Mutlu
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D005091:Exons; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D008268:Macular Degeneration / Q000151:congenital* / Q000235:genetics; D008297:Male; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D000080362:Stargardt Disease
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters
keywords: ABCA4; STGD1; Stargardt; deep-intronic variants; mutation; retinal dystrophies; splicing