Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling |
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| Institution: | 1. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;2. Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, MI;3. GeneDx, Gaithersburg, MD;4. Center for Precision Health Research, National Human Genome Research Institute, Bethesda, MD;5. Department of Health, Behavior and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;6. Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;7. Brain Development Research Program, Department of Neurology, University of California San Francisco, San Francisco, CA;8. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA;9. Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA;10. Division of Pediatric Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota;11. Institute of Human Genetics, Technical University Munich School of Medicine, Munich, Germany;12. Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany;13. Division of Pediatric Neurology, Department of Pediatrics, Dr. von Hauner Children’s Hospital, LMU University Hospital, Munich, Germany;14. Division of Child Neurology and Inherited Metabolic Diseases, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany;15. Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France;16. Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Rondebosch, South Africa;17. Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA;18. Division of Child and Adolescent Neurology, The University of Texas Health Science Center, Houston, TX;19. Division of Genetics, Birth Defects, and Metabolism, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;20. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL;21. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;22. Division of Dysmorphology & Teratology, Department of Pediatrics, University of California San Diego, San Diego, CA;23. Division of Genetics/ Dysmorphology, Rady Children''s Hospital San Diego, San Diego, CA;24. Division of Genetics, McMaster Children''s Hospital, Hamilton, Ontario, Canada;25. Department of Pediatrics, Penn State Health Children’s Hospital, Hershey, PA;26. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI;27. Division of Genetics and Genomics, Massachusetts General Hospital, Harvard Medical School, Boston, MA;28. Division of Pulmonary Medicine, Boston Children''s Hospital and Harvard Medical School, Boston, MA;29. Channing Division of Network Medicine, Department of Medicine, Brigham and Women''s Hospital and Harvard Medical School, Boston, MA;30. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women''s Hospital and Harvard Medical School, Boston, MA;1. Human Genetics and Genetic Counseling Master''s Program, Stanford Medicine, Stanford, CA;2. Stanford Hospitals and Clinics Genetic Testing Optimization Service, Stanford Medicine, Stanford, CA;3. Department of Pathology, Stanford University, Stanford, CA;4. Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA;5. Quantitative Sciences Unit, Stanford University, Palo Alto, CA;1. Division of Pediatric Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX;2. Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, TX;3. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School at Brown University, Providence, RI;4. Division of Vascular Surgery, Department of Surgery, University of Washington, Seattle, WA;5. Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX;1. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA;2. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA;3. Division of Biostatistics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, MD;4. Department of Mathematical Sciences, Tsinghua University, Beijing, China;5. Department of Computer Science, School of Engineering, Tufts University, Medford, MA;6. Cancer Genetics and Prevention Division, Dana-Farber Cancer Institute, Boston, MA;7. Division of Gastroenterology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA;8. McGraw/Patterson Center for Population Sciences, Dana-Farber Cancer Institute, Boston, MA;9. Department of Pathology and Laboratory Medicine, Molecular Diagnostic Service, Memorial Sloan Kettering Cancer Center, New York, NY;10. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Comprehensive Cancer Center, New York, NY;11. Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY;12. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX;13. Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX;14. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX;15. Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX;16. Nokia Bell Labs, Murray Hill, NJ;17. Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD;18. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia;19. University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia;20. Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia;21. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia;22. University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia;23. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia;24. Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia;25. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia;26. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA;1. Medical Genetics Service, Gaffrée and Guinle University Hospital, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil;2. D’Or Institute of Research and Education (IDOR), Rio de Janeiro, Brazil;3. Centro de Genética Médica do Rio de Janeiro, Rio de Janeiro, Brazil;4. Birth Defects Epidemiology Laboratory, Oswaldo Cruz Institute, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;1. Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;3. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX;4. Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;5. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China;6. Department of Gynecology and Obstetrics, Research Centre for Women''s Health, Tübingen University Hospital, Tübingen, Germany;7. Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China;8. Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China;9. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland;10. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;11. Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;12. Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;13. Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;14. Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children''s Hospital, Athens, Greece;15. Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion Hospital, Athens, Greece;16. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil;17. Department of Pediatrics, Baylor College of Medicine, Houston, TX;18. Department of Obstetrics and Gynecology, Texas Children''s Hospital and Baylor College of Medicine, Houston, TX;19. Texas Children''s Hospital, Houston, TX;20. Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Athens, Greece;21. Baylor Genetics, Houston, TX;22. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland |
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| Abstract: | PurposeNonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.MethodsAn international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.ResultsWe identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length.ConclusionThese data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis. |
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| Keywords: | Hedgehog signaling MYH10 Neurodevelopmental disorder Nonmuscle myosin Primary cilia |
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