ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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97 citing papers in PubMed, 140 citations in OpenAlex.
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37 more citing papers are in PubMed but not listed here.
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Authors and funding
75 authors at 20 institutions in 21 countries.
Mubeen KhanDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Stéphanie S CornelisDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Marta Del Pozo-ValeroDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Laura WhelanThe School of Genetics & Microbiology, Trinity College Dublin, Dublin, Ireland.
Esmee H RunhartDonders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Ketan MishraDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Femke BultsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Yahya AlSwaitiSt John of Jerusalem Eye Hospital Group, East Jerusalem, Palestine.
Alaa AlTalbishiSt John of Jerusalem Eye Hospital Group, East Jerusalem, Palestine.
Elfride De BaereCenter for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
Sandro BanfiDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples and Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Eyal BaninDepartment of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Miriam BauwensCenter for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.
Tamar Ben-YosefRuth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Camiel J F BoonDepartment of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
L Ingeborgh van den BornThe Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Sabine DefoortService d'exploration de la vision et neuro-ophtalmologie, Centre Hospitalier Universitaire de Lille, Lille, France.
Aurore DevosUniv. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000, Lille, France.
Adrian DockeryThe School of Genetics & Microbiology, Trinity College Dublin, Dublin, Ireland.
Lubica DudakovaResearch Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Ana FakinEye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.
G Jane FarrarThe School of Genetics & Microbiology, Trinity College Dublin, Dublin, Ireland.
Juliana Maria Ferraz SallumDepartment of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Kaoru FujinamiUCL Institute of Ophthalmology, London, UK.
Christian GilissenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Damjan GlavačDepartment of Molecular Genetics, Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia.
Michael B GorinDepartment of Ophthalmology, David Geffen School of Medicine, Stein Eye Institute, University of California-Los Angeles, Los Angeles, CA, USA.
Jacquie GreenbergUniversity 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.
Takaaki HayashiDepartment of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.
Ymkje M HettingaBartiméus Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands.
Alexander HoischenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Carel B HoyngDonders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Karsten HufendiekUniversity Eye Hospital Hannover Medical School, Hannover, Germany.
Herbert JägleDepartment of Ophthalmology, University Hospital, University Regensburg, Regensburg, Germany.
Smaragda KamakariOphthalmic Genetics Unit, OMMA Ophthalmological Institute of Athens, Athens, Greece.
Marianthi KaraliDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Naples and Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
Ulrich KellnerRare Retinal Disease Center, AugenZentrum Siegburg, MVZ ADTC Siegburg GmbH, Siegburg, Germany.
Caroline C W KlaverDepartment of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Bohdan KousalResearch Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Tina M LameyCentre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, Australia.
Ian M MacDonaldDepartments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, AB, Canada.
Anna MatyniaDepartment of Ophthalmology, David Geffen School of Medicine, Stein Eye Institute, University of California-Los Angeles, Los Angeles, CA, USA.
Terri L McLarenCentre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, Australia.
Marcela D MenaLaboratory of Molecular and Cellular Therapy, Fundacion Instituto Leloir-CONICET, Buenos Aires, Argentina.
Isabelle MeunierInstitut des Neurosciences de Montpellier, INSERM, Université de Montpellier, Montpellier, France.
Rianne MillerDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Hadas NewmanDepartment of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Buhle NtoziniUniversity 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.
Monika OldakDepartment of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland.
Marc PieterseDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Osvaldo L PodhajcerLaboratory of Molecular and Cellular Therapy, Fundacion Instituto Leloir-CONICET, Buenos Aires, Argentina.
Bernard PuechService d'exploration de la vision et neuro-ophtalmologie, Centre Hospitalier Universitaire de Lille, Lille, France.
Raj RamesarUniversity 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.
Klaus RütherAugenarztpraxis, Dorotheenstraße, Berlin, Germany.
Manar SalamehSt John of Jerusalem Eye Hospital Group, East Jerusalem, Palestine.
Mariana Vallim SallesDepartment of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Dror SharonDepartment of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Francesca SimonelliEye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
Georg SpitalDepartment of Ophthalmology, St. Franziskus-Hospital, Münster, Germany.
Marloes SteehouwerDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Jacek P SzaflikDepartment of Ophthalmology, Medical University of Warsaw SPKSO Ophthalmic University Hospital, Warsaw, Poland.
Jennifer A ThompsonAustralian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Caroline ThuillierCHU Lille, Institut de Génétique Médicale, Lille, France.
Anna M TracewskaDNA Analysis Unit, ŁUKASIEWICZ Research Network-PORT Polish Center for Technology Development, Wroclaw, Poland.
Martine van ZweedenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Andrea L VincentDepartment of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand.
Xavier ZanlonghiCentre de Compétence Maladie Rare, Clinique Jules Verne, Nantes, France.
Petra LiskovaResearch Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Heidi StöhrInstitute of Human Genetics, University of Regensburg, Regensburg, Germany.
John N De RoachCentre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA, Australia.
Carmen AyusoDepartment of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
Lisa RobertsUniversity 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.
Bernhard H F WeberInstitute of Human Genetics, University of Regensburg, Regensburg, Germany.
Claire-Marie Dhaenens *Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M Cremers *Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. frans.cremers@radboudumc.nl.ORCID http://orcid.org/0000-0002-4954-5592
Radboud University Nijmegen · NLUniversity of Cape Town · ZACentre Hospitalier Universitaire de Lille · FRCharles University · CZSt John of Jerusalem Eye Hospital Group · ILThe University of Western Australia · AUTrinity College Dublin · IEUniversity of Campania "Luigi Vanvitelli" · ITConsejo Nacional de Investigaciones Científicas y Técnicas · ARGhent University Hospital · BEHebrew University of Jerusalem · ILInserm · FRMedical University of Warsaw · PLUniversidade Federal de São Paulo · BRUniversity of California, Los Angeles · USUniversity of Regensburg · DEAlacris (Germany) · DEBartiméus · NLCentre for Biomedical Network Research on Rare Diseases · ESClinique Jules Verne · FR
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
Indexed as
Macular DegenerationTranscriptomeATP-Binding Cassette TransportersGenomicsHumansIntronsMutationPedigreeStargardt DiseaseABCA4 protein, humanATP-Binding Cassette TransportersABCA4deep-intronic variantssmMIPsStargardt diseasestructural variants
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