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Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

  • Khan, Mubeen1, 1
  • Cornelis, Stéphanie S.1, 1
  • Pozo-Valero, Marta Del1, 2
  • Whelan, Laura3
  • Runhart, Esmee H.1, 1
  • Mishra, Ketan1, 1
  • Bults, Femke1
  • AlSwaiti, Yahya4
  • AlTalbishi, Alaa4
  • De Baere, Elfride5
  • Banfi, Sandro6
  • Banin, Eyal7
  • Bauwens, Miriam5
  • Ben-Yosef, Tamar8
  • Boon, Camiel J. F.9, 10
  • van den Born, L. Ingeborgh11, 12
  • Defoort, Sabine13
  • Devos, Aurore14
  • Dockery, Adrian3
  • Dudakova, Lubica15
  • And 55 more
  • 1 Radboud University Medical Center, Nijmegen, The Netherlands , Nijmegen (Netherlands)
  • 2 IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain , Madrid (Spain)
  • 3 Trinity College Dublin, Dublin, Ireland , Dublin (Ireland)
  • 4 St John of Jerusalem Eye Hospital Group, East Jerusalem, Palestine , East Jerusalem (Palestinian Territories)
  • 5 Ghent University and Ghent University Hospital, Ghent, Belgium , Ghent (Belgium)
  • 6 University of Campania Luigi Vanvitelli, Naples and Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy , Pozzuoli (Italy)
  • 7 The Hebrew University of Jerusalem, Jerusalem, Israel , Jerusalem (Israel)
  • 8 Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel , Haifa (Israel)
  • 9 Leiden University Medical Center, Leiden, The Netherlands , Leiden (Netherlands)
  • 10 Amsterdam University Medical Centers, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 11 The Rotterdam Eye Hospital, Rotterdam, The Netherlands , Rotterdam (Netherlands)
  • 12 The Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands , Rotterdam (Netherlands)
  • 13 Centre Hospitalier Universitaire de Lille, Lille, France , Lille (France)
  • 14 Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, F-59000, France , Lille (France)
  • 15 Charles University and General University Hospital in Prague, Prague, Czech Republic , Prague (Czechia)
  • 16 Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia , Ljubljana (Slovenia)
  • 17 Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil , São Paulo (Brazil)
  • 18 Instituto de Genética Ocular, São Paulo, SP, Brazil , São Paulo (Brazil)
  • 19 UCL Institute of Ophthalmology, London, UK , London (United Kingdom)
  • 20 Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan , Tokyo (Japan)
  • 21 Keio University, Tokyo, Japan , Tokyo (Japan)
  • 22 Moorfields Eye Hospital, London, UK , London (United Kingdom)
  • 23 Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia , Ljubljana (Slovenia)
  • 24 University of California–Los Angeles, Los Angeles, CA, USA , Los Angeles (United States)
  • 25 University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa , Cape Town (South Africa)
  • 26 The Jikei University School of Medicine, Tokyo, Japan , Tokyo (Japan)
  • 27 Bartiméus Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands , Zeist (Netherlands)
  • 28 University Eye Hospital Hannover Medical School, Hannover, Germany , Hannover (Germany)
  • 29 University Hospital, University Regensburg, Regensburg, Germany , Regensburg (Germany)
  • 30 Ophthalmic Genetics Unit, OMMA Ophthalmological Institute of Athens, Athens, Greece , Athens (Greece)
  • 31 Rare Retinal Disease Center, AugenZentrum Siegburg, MVZ ADTC Siegburg GmbH, Siegburg, Germany , Siegburg (Germany)
  • 32 RetinaScience, Bonn, Germany , Bonn (Germany)
  • 33 Erasmus Medical Centre, Rotterdam, The Netherlands , Rotterdam (Netherlands)
  • 34 The University of Western Australia, Nedlands, WA, Australia , Nedlands (Australia)
  • 35 Sir Charles Gairdner Hospital, Nedlands, WA, Australia , Nedlands (Australia)
  • 36 University of Alberta, Edmonton, AB, Canada , Edmonton (Canada)
  • 37 Fundacion Instituto Leloir-CONICET, Buenos Aires, Argentina , Buenos Aires (Argentina)
  • 38 Université de Montpellier, Montpellier, France , Montpellier (France)
  • 39 Tel Aviv Sourasky Medical Center, Tel Aviv, Israel , Tel Aviv (Israel)
  • 40 Tel Aviv University, Tel Aviv, Israel , Tel Aviv (Israel)
  • 41 Medical University of Warsaw, Warsaw, Poland , Warsaw (Poland)
  • 42 Augenarztpraxis, Dorotheenstraße, Berlin, Germany , Berlin (Germany)
  • 43 University of Campania Luigi Vanvitelli, Naples, Italy , Naples (Italy)
  • 44 St. Franziskus-Hospital, Münster, Germany , Münster (Germany)
  • 45 Medical University of Warsaw SPKSO Ophthalmic University Hospital, Warsaw, Poland , Warsaw (Poland)
  • 46 CHU Lille, Institut de Génétique Médicale, Lille, France , Lille (France)
  • 47 DNA Analysis Unit, ŁUKASIEWICZ Research Network—PORT Polish Center for Technology Development, Wroclaw, Poland , Wroclaw (Poland)
  • 48 The University of Auckland, Grafton, Auckland, New Zealand , Auckland (New Zealand)
  • 49 Auckland District Health Board, Auckland, New Zealand , Auckland (New Zealand)
  • 50 Clinique Jules Verne, Nantes, France , Nantes (France)
  • 51 University of Regensburg, Regensburg, Germany , Regensburg (Germany)
Published Article
Genetics in Medicine
Springer Nature
Publication Date
Apr 20, 2020
DOI: 10.1038/s41436-020-0787-4
Springer Nature


PurposeMissing 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.MethodsSequencing 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.ResultsIn 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.ConclusionDeep 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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