Heterozygous Deep‐Intronic Variants and Deletions in ABCA4 in Persons with Retinal Dystrophies and One Exonic ABCA4 Variant |
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| Authors: | 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 |
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| Affiliation: | 1. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands;2. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;3. The Rotterdam Eye Hospital, Rotterdam, The Netherlands;4. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands;5. Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, Iowa;6. Department of Biomedical Engineering, The University of Iowa Carver College of Medicine, Iowa City, Iowa;7. Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa;8. Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands;9. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands |
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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. |
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| Keywords: | ABCA4 Stargardt STGD1 retinal dystrophies splicing deep‐intronic variants mutation |
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