ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 37 citations in OpenAlex.
- Article
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- Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies.Cancer cell international · 2024Review
- Biallelic variants in Plexin B2 (Journal of medical genetics · 2024Article
- Tribal FounderNeurology. Genetics · 2024Article
- Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.NPJ genomic medicine · 2024Article
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- Allelic heterogeneity and abnormal vesicle recycling inFrontiers in molecular neuroscience · 2024Article
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- The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.Genes · 2023Review
- Semaphorin-6D and Plexin-A1 Act in a Non-Cell-Autonomous Manner to Position and Target Retinal Ganglion Cell Axons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Rare variant analysis ofGenes & diseases · 2023Article
- Genes4Epilepsy: An epilepsy gene resource.Epilepsia · 2023Article
- Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.American journal of human genetics · 2023Article
- Neuroimaging features of WOREE syndrome: a mini-review of the literature.Frontiers in pediatrics · 2023Review
- Neuroimaging in PRUNE1 syndrome: a mini-review of the literature.Frontiers in neurology · 2023Review
- The therapeutic effects of physical treatment for patients with hereditary spastic paraplegia: a narrative review.Frontiers in neurology · 2023Review
- A Novel Loss-of-FunctionInternational journal of molecular sciences · 2022Article
- Neurogenetic disorders across the lifespan: from aberrant development to degeneration.Nature reviews. Neurology · 2022Review
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Authors and funding
66 authors at 20 institutions in 11 countries.
Gabriel C Dworschak *Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany. gabriel.dworschak@uni-bonn.de.ORCID 0000-0003-0015-6964
Jaya Punetha *Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jeshurun C KalanithyInstitute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
Enrico MingardoInstitute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
Haktan B ErdemDepartment of Medical Genetics, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey.
Zeynep C AkdemirDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Ender KaracaDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Tadahiro MitaniDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Dana MarafiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jawid M FatihDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Shalini N JhangianiHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Jill V HunterDepartment of Radiology, Baylor College of Medicine, Houston, TX, USA.
Tikam Chand DakalGenome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India.
Bhanupriya DhabhaiGenome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India.
Omar DabbaghDepartment of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hessa S AlsaifDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Fowzan S AlkurayaDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Reza MaroofianDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Henry HouldenDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Natalia DominikDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Vincenzo SalpietroDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Tipu SultanDepartment of Pediatric Neurology, Institute of Child Health, The Children's Hospital Lahore, Lahore, Pakistan.
Shahzad HaiderDepartment of Paediatric Medicine, Wah Medical College, Rawalpindi, Pakistan.
Farah BibiUniversity Institute of Biochemistry & Biotechnology, PMAS - Arid Agriculture University, Rawalpindi, Pakistan.
Holger ThieleCologne Center for Genomics, University of Cologne, Cologne, Germany.
Julia HoefeleInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Korbinian M RiedhammerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Matias WagnerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Ilaria GuellaDepartment of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.
Michelle DemosDivision of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC, Canada.
Boris KerenAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Julien BurattiAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Perrine CharlesAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Caroline NavaAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Delphine HéronAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Solveig HeideAP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, Paris, France.
Elise ValkanasCenter for Mendelian Genomics, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Leigh B WaddellKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Kristi J JonesKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Emily C OatesKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Sandra T CooperKids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Daniel MacArthurBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
Steffen SyrbeDivision of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Andreas ZieglerDivision of Pediatric Neurology and Metabolic Medicine, Centre for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Volkan OkurDepartment of Pediatrics, Columbia University, New York, NY, USA.
Wendy K ChungDepartment of Pediatrics, Columbia University, New York, NY, USA.
Sarah A O'SheaDepartment of Neurology, Columbia University, New York, NY, USA.
Roy AlcalayDepartment of Neurology, Columbia University, New York, NY, USA.
Stanley FahnDepartment of Neurology, Columbia University, New York, NY, USA.
Paul R MarkDivision of Medical Genetics, Helen DeVos Children's Hospital Grand Rapids, New York, MI, USA.
Renzo GuerriniNeuroscience Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
Annalisa VetroNeuroscience Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
Beth HudsonGeneDx, Gaithersburg, MD, USA.
Rhonda E SchnurGeneDx, Gaithersburg, MD, USA.
George E HogansonDepartment of Pediatrics, University of Illinois, College of Medicine, Chicago, IL, USA.
Jennifer E BurtonDepartment of Pediatrics, University of Illinois, College of Medicine, Peoria, IL, USA.
Meriel McEntagartSouth West Thames Regional Genetics Centre, St. George's Healthcare NHS Trust, St. George's, University of London, London, United Kingdom.
Tobias LindenbergInstitute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.
Öznur YilmazInstitute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.
Benjamin OdermattInstitute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.
Davut PehlivanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jennifer E PoseyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Heiko ReutterInstitute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
Baylor College of Medicine · USUniversity of Bonn · DEColumbia University · USNational Hospital for Neurology and Neurosurgery · GBSorbonne Université · FRThe University of Sydney · AUTUM Klinikum · DEBroad Institute · USHeidelberg University · DEIllinois College · USKing Faisal Specialist Hospital & Research Centre · SAMeyer Children's Hospital · ITMohanlal Sukhadia University · INUniversity of British Columbia · CAAlfaisal University · SACentre National de la Recherche Scientifique · FRChildren's Hospital at Westmead · AUHelen DeVos Children's Hospital · USLeipzig University · DEPir Mehr Ali Shah Arid Agriculture University · PK
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MIndividual genomic analyses to discover the molecular basis and mechanisms contributing to adult-onset diseaseK08HG008986 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI POSEY, JENNIFER ELLEN · 2017 to 2021
$831kMedical Research Council G0601943Medical Research Council MR/S005021/1Medical Research Council MR/S01165X/1NCATS NIH HHS UL1 TR001863NHGRI NIH HHS K08 HG008986NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG006542NHGRI NIH HHS UM1 HG008900NINDS NIH HHS R35 NS105078Wellcome Trust
Abstract
purposeTo investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.
methodsWe assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.
resultsShared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye.
conclusionWe propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Indexed as
Eye AbnormalitiesNeurodevelopmental DisordersAnimalsGenetic Association StudiesHumansNerve Tissue ProteinsPhenotypeReceptors, Cell SurfaceZebrafishNerve Tissue ProteinsPLXNA1 protein, humanReceptors, Cell Surface
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