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An Augmented ABCA4 Screen Targeting Noncoding Regions Reveals a Deep Intronic Founder Variant in Belgian Stargardt Patients |
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| Authors: | Miriam Bauwens Julie De Zaeytijd Nicole Weisschuh Susanne Kohl Françoise Meire Karin Dahan Fanny Depasse Sarah De Jaegere Thomy De Ravel Marjan De Rademaeker Bart Loeys Frauke Coppieters Bart P. Leroy Elfride De Baere |
| Affiliation: | 1. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium;2. Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium;3. Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany;4. Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium;5. Centre de génétique humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium;6. Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium;7. Center for Medical Genetics, Free University of Brussels, Brussels, Belgium;8. Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium;9. Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania |
| Abstract: | Autosomal‐recessive Stargardt disease (STGD1) is hallmarked by a large proportion of patients with a single heterozygous causative variant in the disease gene ABCA4. Braun et al. ( 2013 ) reported deep intronic variants of ABCA4 in STGD1 patients with one coding variant, prompting us to perform an augmented screen in 131 Belgian STGD1 patients with one or no ABCA4 variant to uncover deep intronic causal ABCA4 variants. This revealed a second variant in 28.6% of cases. Twenty‐six percent of these carry the same causal variant c.4539+2001G>A (V4). Haplotyping in V4 carriers showed a common region of 63 kb, suggestive of a founder mutation. Genotype–phenotype correlations suggest a moderate‐to‐severe impact of V4 on the STGD1 phenotype. In conclusion, V4 occurs in a high fraction of Belgian STGD1 patients and represents the first deep intronic founder mutation in ABCA4. This emphasizes the importance of augmented molecular genetic testing of ABCA4 in Belgian STGD1. |
| Keywords: | Stargardt STGD1 ABCA4 deep intronic mutation founder genotype– phenotype correlations |