ArticleAmerican journal of human genetics2021
Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10citing papers in PubMed
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10 citing papers in PubMed, 15 citations in OpenAlex.
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Authors and funding
48 authors at 20 institutions in 10 countries.
Holger HengelDepartment of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.
Shabab B HannanDepartment of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.
Sarah DyackDivision of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada.
Sara B MacKayMaritime Medical Genetics Service IWK Health Centre, Halifax, NS B3R 6R8 Canada.
Ulrich SchatzInstitute of Human Genetics, Medical University of Innsbruck, Peter-Mayr. Str. 1, 6020 Innsbruck, Austria; Institute of Human Genetics, Technical University of Munich, Trogerstr. 32, 81675 Munich, Germany.
Martin FlegerDepartment of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900 Bregenz, Austria.
Andreas KurringerDepartment of Pediatrics, Landeskrankenhaus Bregenz, Carl-Pedenz-Str. 2, 6900 Bregenz, Austria.
Ghassan BaloushaDepartment of Pathology and Histology, Al-Quds University, Eastern Jerusalem 19356, Palestine.
Zaid GhanimPalestine Medical Complex, Ramallah, Palestine.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
Hamad AlzaidanDepartment of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia.
Hessa S AlsaifDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Tadahiro MitaniDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Sevcan BozdoganDepartment of Medical Genetics, Cukurova University Faculty of Medicine, 01330 Adana, Turkey.
Davut PehlivanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Joseph J GleesonLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Mohammadreza DehghaniMedical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Mohammad Y V MehrjardiAbortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Elliott H SherrDepartment of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Kendall C ParksDepartment of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Emanuela ArgilliDepartment of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Amber BegtrupGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Hamid GalehdariDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Osama BaloushaFaculty of Medicine, Al-Quds University, Eastern Jerusalem 19356, Palestine.
Gholamreza ShariatiDepartment of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Neda MazaheriDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Reza A MalamiriDepartment of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Alistair T PagnamentaNational Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Helen KingstonManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
Siddharth BankaManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.
Adam JacksonDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester M13 9WL, UK.
Mathew OsmondChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Care4Rare Canada ConsortiumChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Genomics England Research ConsortiumGenomics England, London EC1M 6BQ, UK.
Angelika RießInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
Thomas NägeleDepartment of Neuroradiology, University Hospital of Tuebingen, 72076 Tübingen, Germany.
Stefanie SchusterDepartment of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.
Stefan HauserDepartment of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany.
Jakob AdmardInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; NGS Competence Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
Nicolas CasadeiInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; NGS Competence Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
Ana VelicProteome Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
Boris MacekProteome Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
Stephan OssowskiInstitute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; NGS Competence Center Tübingen, University of Tübingen, 72076 Tübingen, Germany.
Henry HouldenDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Reza MaroofianDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK. Electronic address: rmaroofian@gmail.com.
Ludger SchölsDepartment of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany; German Center of Neurodegenerative Diseases, 72076 Tübingen, Germany. Electronic address: ludger.schoels@uni-tuebingen.de.
German Center for Neurodegenerative Diseases · DEUniversity of Tübingen · DEBaylor College of Medicine · USBernstein Center for Computational Neuroscience Tübingen · DEUniversity of California, San Francisco · USAhvaz Jundishapur University of Medical Sciences · IRAl-Quds University · PSKing Faisal Specialist Hospital & Research Centre · SALandeskrankenhaus Feldkirch · ATNational Hospital for Neurology and Neurosurgery · GBShahid Chamran University of Ahvaz · IRShahid Sadoughi University of Medical Sciences and Health Services · IRUniversity of Manchester · GBAlfaisal University · SACentre for Human Genetics · GBCukurova University · TRDalhousie University · CAHoward Hughes Medical Institute · USInnsbruck Medical University · ATIzaak Walton Killam Health Centre · CA
Funding
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MDe novo copy number variation and gene discovery in human brain malformationsR01NS058721 · NINDS · UNIVERSITY OF CHICAGO · PI ARGILLI, EMANUELA · 2008 to 2025
$10.9MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MNHGRI NIH HHS UM1 HG006542NINDS NIH HHS R01 NS058721NINDS NIH HHS R35 NS105078Wellcome TrustWellcome Trust WT093205 MAWellcome Trust WT104033AIA
Abstract
BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.
Indexed as
Loss of Function MutationLoss of HeterozygosityAdolescentAdultAnimalsCell MovementChildChild, PreschoolDrosophilaFemaleFibroblastsHumansInfantMaleMiceMice, KnockoutBCAS3 protein, humanNeoplasm ProteinsProteomeBCAS3fibroblastsglobal developmental delaymicrocephalyneurodevelopmental disorderproteomicspyramidal tract involvementthin corpus callosumtranscriptomicsUAS-Gal4
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