Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Nathalie M Bax; Riccardo Sangermano; Susanne Roosing; Alberta A H J Thiadens; Lies H Hoefsloot; L Ingeborgh van den Born; Milan Phan; B Jeroen Klevering; Carla Westeneng-van Haaften; Terry A Braun; Marijke N Zonneveld-Vrieling; Ilse de Wijs; Merve Mutlu; Edwin M Stone; Anneke I den Hollander; Caroline C W Klaver; Carel B Hoyng; Frans P M Cremers

doi:10.1002/humu.22717

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Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Journal article

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Peer reviewed

Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Nathalie M Bax, Riccardo Sangermano, Susanne Roosing, Alberta A H J Thiadens, Lies H Hoefsloot, L Ingeborgh van den Born, Milan Phan, B Jeroen Klevering, Carla Westeneng-van Haaften, Terry A Braun, …

Human mutation, Vol.36(1), pp.43-47

01/2015

DOI: 10.1002/humu.22717

PMID: 25363634

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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.

Sequence Deletion

Genetic Predisposition to Disease

Exons

Introns

Humans

Genetic Association Studies - methods

Retinitis Pigmentosa - genetics

Male

Sequence Analysis, DNA

Genetic Heterogeneity

Macular Degeneration - congenital

ATP-Binding Cassette Transporters - genetics

Macular Degeneration - genetics

Pedigree

Female

High-Throughput Nucleotide Sequencing

Details

Title: Subtitle: Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant
Creators: Nathalie M Bax - Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands
Riccardo Sangermano
Susanne Roosing
Alberta A H J Thiadens
Lies H Hoefsloot
L Ingeborgh van den Born
Milan Phan
B Jeroen Klevering
Carla Westeneng-van Haaften
Terry A Braun
Marijke N Zonneveld-Vrieling
Ilse de Wijs
Merve Mutlu
Edwin M Stone
Anneke I den Hollander
Caroline C W Klaver
Carel B Hoyng
Frans P M Cremers
Resource Type: Journal article
Publication Details: Human mutation, Vol.36(1), pp.43-47
DOI: 10.1002/humu.22717
PMID: 25363634
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Publisher: United States
Grant note: DOI: 10.13039/501100000262, name: Foundation Fighting Blindness, award: BR-GE-0510-04890RAD and C-GE-0811-0545-RAD01; name: FP7-PEOPLE-2012-ITN, award: 317472; DOI: 10.13039/100007044, name: Macula Vision Research Foundation; name: MD Fonds; name: Nijmeegse Oogonderzoek Stichting; name: Prof. Dr. H.J. Flieringa Foundation SWOO
Language: English
Date published: 01/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979931402771

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