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...

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Published in:Human mutation Vol. 36; no. 1; pp. 43 - 47
Main Authors: Bax, Nathalie M., Sangermano, Riccardo, Roosing, Susanne, Thiadens, Alberta A.H.J., Hoefsloot, Lies H., van den Born, L. Ingeborgh, Phan, Milan, Klevering, B. Jeroen, Westeneng-van Haaften, Carla, Braun, Terry A., Zonneveld-Vrieling, Marijke N., de Wijs, Ilse, Mutlu, Merve, Stone, Edwin M., den Hollander, Anneke I., Klaver, Caroline C.W., Hoyng, Carel B., Cremers, Frans P.M.
Format: Journal Article
Language:English
Published: United States Blackwell Publishing Ltd 01.01.2015
John Wiley & Sons, Inc
Subjects:
ABCA4
ATP-Binding Cassette Transporters - genetics
deep-intronic variants
Exons
Eye diseases
Female
Genes
Genetic Association Studies - methods
Genetic counseling
Genetic Heterogeneity
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Introns
Macular Degeneration - congenital
Macular Degeneration - genetics
Male
Mutation
Ophthalmology
Pedigree
retinal dystrophies
Retinitis Pigmentosa - genetics
Sequence Analysis, DNA
Sequence Deletion
splicing
Stargardt
STGD1
Stargardt
mutation
deep-intronic variants
ABCA4
retinal dystrophies
STGD1
splicing
ISSN:1059-7794, 1098-1004, 1098-1004
Online Access:Get full text
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Summary: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. A person with Stargardt disease (STGD1) carries a deletion of exons 20‐22 in one of two ABCA4 gene copies and a deep‐intronic mutation (c.5196+1137G>A) in the other copy. Both types of mutations cannot be identified using standard Sanger sequencing of the protein coding segments of the gene and require specific analyses. Deletions and deep‐intronic variants in ABCA4 can constitute up to 20% of ABCA4 mutations.
Bibliography:ArticleID:HUMU22717
istex:5EEF421A414EC9E7973C4A177353C008A856894B
ark:/67375/WNG-6PPW69W6-B
Foundation Fighting Blindness USA - No. BR-GE-0510-04890RAD
These are shared first authors.
Communicated by Andreas Gal
Susanne Roosing's present address is Howard Hughes Medical Institute, The Rockefeller University, Department for Pediatric Brain Diseases, New York, NY 10021‐6399.
Contract grant sponsors: Foundation Fighting Blindness USA (grants BR‐GE‐0510‐04890RAD, C‐GE‐0811‐0545‐RAD01); FP7‐PEOPLE‐2012‐ITN Programme EyeTN (agreement 317472); The Macula Vision Research Foundation; The Nijmeegse Oogonderzoek Stichting; The Prof. Dr. H.J. Flieringa Foundation SWOO; The Rotterdam Eye Hospital; The MD Fonds and the Stichting A.F. Deutman Researchfonds Oogheelkunde.
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ISSN:1059-7794
1098-1004
1098-1004
DOI:10.1002/humu.22717