Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies |
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| Affiliation: | 1. Institute of Human Genetics, Medical Faculty University of Bonn Bonn Germany;2. Institute of Anatomy and Cell Biology, Medical Faculty University of Bonn Bonn Germany;3. Department of Pediatrics University Hospital Bonn Bonn Germany;4. Department of Molecular and Human Genetics, Baylor College of Medicine Houston TX USA;5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai New York NY USA;6. Department of Medical Genetics University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital Ankara Turkey;7. Department of Genetics University of Alabama at Birmingham Birmingham AL USA;8. Human Genome Sequencing Center, Baylor College of Medicine Houston TX USA;9. Department of Radiology, Baylor College of Medicine Houston TX USA;10. Genome and Computational Biology Lab, Department of Biotechnology Mohanlal Sukhadia University Udaipur Rajasthan India;11. Department of Neuroscience, King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia;12. Department of Genetics, King Faisal Specialist Hospital and Research Centre Riyadh Saudi Arabia;13. Department of Anatomy and Cell Biology, College of Medicine Alfaisal University Riyadh Saudi Arabia;14. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology University College London London United Kingdom;15. Department of Pediatric Neurology, Institute of Child Health, The Children’s Hospital Lahore Lahore Pakistan;16. Department of Paediatric Medicine, Wah Medical College Rawalpindi Pakistan;17. University Institute of Biochemistry & Biotechnology, PMAS – Arid Agriculture University Rawalpindi Pakistan;18. Cologne Center for Genomics University of Cologne Cologne Germany;19. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine Technical University of Munich Munich Germany;20. Department of Nephrology, Klinikum rechts der Isar, School of Medicine Technical University of Munich Munich Germany;21. Institute of Human Genetics, Helmholtz Zentrum München Neuherberg Germany;22. Institute of Neurogenomics, Helmholtz Zentrum München Neuherberg Germany;23. Department of Medical Genetics, Centre for Applied Neurogenetics University of British Columbia Vancouver BC Canada;24. Division of Neurology, Department of Pediatrics University of British Columbia and BC Children’s Hospital Vancouver BC Canada;25. AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique Paris France;26. Institut du Cerveau et de la Moelle épinière, Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225 Paris France;27. Center for Mendelian Genomics, The Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge MA USA;28. Kids Neuroscience Centre, Kids Research, The Children’s Hospital at Westmead Sydney NSW Australia;29. Discipline of Child and Adolescent Health, Sydney Medical School University of Sydney Sydney NSWAustralia;30. School of Biotechnology and Biomolecular Sciences, Faculty of Science The University of New South Wales Sydney NSW Australia;31. Children’s Medical Research Institute Westmead NSW Australia;32. Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA USA;33. Analytic and Translational Genetics Unit, Massachusetts General Hospital Boston MA USA;34. Harvard Medical School Boston MA USA;35. Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany;36. Division of Pediatric Neurology and Metabolic Medicine, Centre for Pediatrics and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany;37. Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany;38. Department of Pediatrics Columbia University New York NY USA;39. Department of Neurology Columbia University New York NY USA;40. Division of Medical Genetics, Helen DeVos Children’s Hospital Grand Rapids New York MI USA;41. Neuroscience Department Children’s Hospital A. Meyer-University of Florence Florence Italy;42. GeneDx Gaithersburg MD USA;43. Department of Pediatrics University of Illinois, College of Medicine Chicago IL USA;44. Department of Pediatrics University of Illinois, College of Medicine Peoria IL USA;45. South West Thames Regional Genetics Centre, St. George’s Healthcare NHS TrustSt. George’s, University of London London United Kingdom;46. Institute of Neuroanatomy, Medical Faculty University of Bonn Bonn Germany;47. Section of Neurology, Department of Pediatrics Baylor College of Medicine Houston TX USA;48. Texas Children’s Hospital Houston TX USA;49. Department of Pediatrics Baylor College of Medicine Houston TX USA;50. Department of Neonatology and Pediatric Intensive Care University Hospital Bonn Bonn Germany;1. Institute of Human Genetics, Medical Faculty University of Bonn Bonn Germany;2. Institute of Anatomy and Cell Biology, Medical Faculty University of Bonn Bonn Germany;3. Department of Pediatrics University Hospital Bonn Bonn Germany;4. Department of Molecular and Human Genetics, Baylor College of Medicine Houston TX USA;5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai New York NY USA;6. Department of Medical Genetics University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital Ankara Turkey;7. Department of Genetics University of Alabama at Birmingham Birmingham AL USA;8. Human Genome Sequencing Center, Baylor College of Medicine Houston TX USA;9. Department of Radiology, Baylor College of Medicine Houston TX USA;10. Genome and Computational Biology Lab, Department of Biotechnology Mohanlal Sukhadia University Udaipur Rajasthan India;11. Department of Neuroscience, King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia;12. Department of Genetics, King Faisal Specialist Hospital and Research Centre Riyadh Saudi Arabia;13. Department of Anatomy and Cell Biology, College of Medicine Alfaisal University Riyadh Saudi Arabia;14. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology University College London London United Kingdom;15. Department of Pediatric Neurology, Institute of Child Health, The Children’s Hospital Lahore Lahore Pakistan;16. Department of Paediatric Medicine, Wah Medical College Rawalpindi Pakistan;17. University Institute of Biochemistry & Biotechnology, PMAS – Arid Agriculture University Rawalpindi Pakistan;18. Cologne Center for Genomics University of Cologne Cologne Germany;19. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine Technical University of Munich Munich Germany;20. Department of Nephrology, Klinikum rechts der Isar, School of Medicine Technical University of Munich Munich Germany;21. Institute of Human Genetics, Helmholtz Zentrum München Neuherberg Germany;22. Institute of Neurogenomics, Helmholtz Zentrum München Neuherberg Germany;23. Department of Medical Genetics, Centre for Applied Neurogenetics University of British Columbia Vancouver BC Canada;24. Division of Neurology, Department of Pediatrics University of British Columbia and BC Children’s Hospital Vancouver BC Canada;25. AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique Paris France;26. Institut du Cerveau et de la Moelle épinière, Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225 Paris France;27. Center for Mendelian Genomics, The Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge MA USA;28. Kids Neuroscience Centre, Kids Research, The Children’s Hospital at Westmead Sydney NSW Australia;29. Discipline of Child and Adolescent Health, Sydney Medical School University of Sydney Sydney NSWAustralia;30. School of Biotechnology and Biomolecular Sciences, Faculty of Science The University of New South Wales Sydney NSW Australia;31. Children’s Medical Research Institute Westmead NSW Australia;32. Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA USA;33. Analytic and Translational Genetics Unit, Massachusetts General Hospital Boston MA USA;34. Harvard Medical School Boston MA USA;35. Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany;36. Division of Pediatric Neurology and Metabolic Medicine, Centre for Pediatrics and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany;37. Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany;38. Department of Pediatrics Columbia University New York NY USA;39. Department of Neurology Columbia University New York NY USA;40. Division of Medical Genetics, Helen DeVos Children’s Hospital Grand Rapids New York MI USA;41. Neuroscience Department Children’s Hospital A. Meyer-University of Florence Florence Italy;42. GeneDx Gaithersburg MD USA;43. Department of Pediatrics University of Illinois, College of Medicine Chicago IL USA;44. Department of Pediatrics University of Illinois, College of Medicine Peoria IL USA;45. South West Thames Regional Genetics Centre, St. George’s Healthcare NHS TrustSt. George’s, University of London London United Kingdom;46. Institute of Neuroanatomy, Medical Faculty University of Bonn Bonn Germany;47. Section of Neurology, Department of Pediatrics Baylor College of Medicine Houston TX USA;48. Texas Children’s Hospital Houston TX USA;49. Department of Pediatrics Baylor College of Medicine Houston TX USA;50. Department of Neonatology and Pediatric Intensive Care University Hospital Bonn Bonn Germany |
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| 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. |
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