Journal
GENETICS IN MEDICINE
Volume 22, Issue 7, Pages 1235-1246Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-0787-4
Keywords
ABCA4; Stargardt disease; smMIPs; deep-intronic variants; structural variants
Categories
Funding
- RetinaUK [GR591]
- Fighting Blindness Ireland grant [FB18CRE]
- Horizon 2020, Marie SklodowskaCurie Innovative Training Network
- Frequent Inherited Blinding Disorder-StarT [813490]
- Foundation Fighting Blindness USA [PPA-0517-0717-RAD]
- Rotterdamse Stichting Blindenbelangen
- Stichting Blindenhulp
- Landelijke Stichting voor Blinden en Slechtzienden
- Macula Degeneratie fonds
- Stichting Blinden-Penning
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Stichting tot Verbetering van het Lot der Blinden
- Groupement de Cooperation Sanitaire Interregional G4 qui reunit les Centres Hospitaliers Universitaires Amiens, Caen, Lille et Rouen (GCS G4)
- Fondation Stargardt France
- Federal Ministry of Education and Research (BMBF) [01GM0851, 01GM1108B]
- Charles University [SVV 260516, UNCE 204064, PROGRES-Q26/LF1]
- Fighting Blindness Ireland
- Health Research Board of Ireland
- Medical Research Charities Group [MRCG-201614]
- Ghent University Research Fund [BOF15/GOA/011]
- Research Foundation Flanders (FVO) [G0C6715N]
- Hercules foundation [AUGE/13/023]
- JED Foundation
- FWO
- funds for Research in Ophthalmology (FRO)
- FWO [1802215N, 1802220N]
- Conchita Rabago Foundation
- Boehringer Ingelheim Fonds
- ISCIII - European Regional Development Fund (ERDF) [PI16/0425]
- RAREGenomics-CM (CAM) [B2017/BMD-3721]
- ONCE
- Ramon Areces Foundation
- Peace for Sight grant
- Retina South Africa
- South African Medical Research Council (MRC)
- Foundation Fighting Blindness [BR-GE-0214-0639-TECH, BR-GE-0518-0734TECH]
- Israeli Ministry of Health [3-12583Q4]
- Olive Young Fund, University Hospital Foundation, Edmonton
- National Science Center (Poland) [N N402 591640, 5916/B/P01/2011/40, UMO-2015/19/D/NZ2/03193]
- Italian Fondazione Roma
- Italian Telethon Foundation
- Ministero dell'Istruzione del l'Universita e della Ricerca (MIUR) under PRIN 2015
- Daljit S. and Elaine Sarkaria Charitable Foundation
- [AZV NU20-07-00182]
- [AZV NU20-0700182]
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Purpose Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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