Journal
HUMAN MUTATION
Volume 36, Issue 1, Pages 43-47Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.22717
Keywords
ABCA4; Stargardt; STGD1; retinal dystrophies; splicing; deep-intronic variants; mutation
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Funding
- Foundation Fighting Blindness USA [BR-GE-0510-04890RAD, C-GE-0811-0545-RAD01]
- FP7-PEOPLE-ITN Programme EyeTN [317472]
- Macula Vision Research Foundation
- Nijmeegse Oogonderzoek Stichting
- Prof. Dr. H.J. Flieringa Foundation SWOO
- Rotterdam Eye Hospital
- MD Fonds
- Stichting A.F. Deutman Researchfonds Oogheelkunde
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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.
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