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Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Nicholas Liao

Nat Genet. 2020 Oct;52(10):1046-1056. doi: 10.1038/s41588-020-0695-1. | PubMed

Sheng Chih Jin1,2,3, Sara A Lewis4,5, Somayeh Bakhtiari4,5, Xue Zeng1,2, Michael C Sierant1,2, Sheetal Shetty4,5, Sandra M Nordlie4,5, Aureliane Elie4,5, Mark A Corbett6, Bethany Y Norton4,5, Clare L van Eyk6, Shozeb Haider7, Brandon S Guida4,5, Helen Magee4,5, James Liu4,5, Stephen Pastore8, John B Vincent8, Janice Brunstrom-Hernandez9, Antigone Papavasileiou10, Michael C Fahey11, Jesia G Berry6, Kelly Harper6, Chongchen Zhou12, Junhui Zhang1, Boyang Li13, Jennifer Heim4, Dani L Webber6, Mahalia S B Frank6, Lei Xia14, Yiran Xu14, Dengna Zhu14, Bohao Zhang14, Amar H Sheth1, James R Knight15, Christopher Castaldi15, Irina R Tikhonova15, Francesc López-Giráldez15, Boris Keren16, Sandra Whalen17, Julien Buratti16, Diane Doummar18, Megan Cho19, Kyle Retterer19, Francisca Millan19, Yangong Wang20, Jeff L Waugh21, Lance Rodan22, Julie S Cohen23, Ali Fatemi23, Angela E Lin24, John P Phillips25, Timothy Feyma26, Suzanna C MacLennan27, Spencer Vaughan28, Kylie E Crompton29, Susan M Reid29, Dinah S Reddihough29, Qing Shang12, Chao Gao30, Iona Novak31, Nadia Badawi31, Yana A Wilson31, Sarah J McIntyre31, Shrikant M Mane15, Xiaoyang Wang14,32, David J Amor29, Daniela C Zarnescu28, Qiongshi Lu33, Qinghe Xing20, Changlian Zhu14,32, Kaya Bilguvar1,15, Sergio Padilla-Lopez4,5, Richard P Lifton1,2, Jozef Gecz6, Alastair H MacLennan6, Michael C Kruer34,35

  1. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  2. Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA.
  3. Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
  4. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
  5. Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
  6. Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
  7. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK.
  8. Molecular Brain Sciences, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  9. One CP Place, Plano, TX, USA.
  10. Division of Paediatric Neurology, Iaso Children's Hospital, Athens, Greece.
  11. Department of Pediatrics, Monash University, Melbourne, Victoria, Australia.
  12. Henan Key Laboratory of Child Genetics and Metabolism, Rehabilitation Department, Children's Hospital of Zhengzhou University, Zhengzhou, China.
  13. Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
  14. Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  15. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
  16. Department of Genetics, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris, France.
  17. UF de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France.
  18. Sorbonne Université, APHP, Service de Neurologie Pédiatrique et Centre de Référence Neurogénétique, Hôpital Armand Trousseau, Paris, France.
  19. GeneDx, Gaithersburg, MD, USA.
  20. Institute of Biomedical Science and Children's Hospital, and Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission (NPFPC), Shanghai Institute of Planned Parenthood Research (SIPPR), IRD, Fudan University, Shanghai, China.
  21. Departments of Pediatrics & Neurology, University of Texas Southwestern and Children's Medical Center of Dallas, Dallas, TX, USA.
  22. Departments of Genetics & Genomics and Neurology, Boston Children's Hospital, Boston, MA, USA.
  23. Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
  24. Medical Genetics, Department of Pediatrics, MassGeneral Hospital for Children, Boston, MA, USA.
  25. Departments of Pediatrics and Neurology, University of New Mexico, Albuquerque, NM, USA.
  26. Division of Pediatric Neurology, Gillette Children's Hospital, St Paul, MN, USA.
  27. Department of Paediatric Neurology, Women's & Children's Hospital, Adelaide, South Australia, Australia.
  28. Departments of Molecular & Cellular Biology and Neuroscience, University of Arizona, Tucson, AZ, USA.
  29. Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia.
  30. Rehabilitation Department, Children's Hospital of Zhengzhou University/Henan Children's Hospital, Zhengzhou, China.
  31. Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia.
  32. Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
  33. Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
  34. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA. kruerm@email.arizona.edu.
  35. Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA. kruerm@email.arizona.edu.

Abstract

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Presented By Sara Lewis | ORCID iD