Rare pathogenic variants in WNK3 cause X-linked intellectual disability

  • Genet Med. 2022 Sep;24(9):1941-1951. doi: 10.1016/j.gim.2022.05.009.
Sébastien Küry  1 ,  Jinwei Zhang  2 ,  Thomas Besnard  3 ,  Alfonso Caro-Llopis  4 ,  Xue Zeng  5 ,  Stephanie M Robert  5 ,  Sunday S Josiah  6 ,  Emre Kiziltug  5 ,  Anne-Sophie Denommé-Pichon  7 ,  Benjamin Cogné  3 ,  Adam J Kundishora  8 ,  Le T Hao  8 ,  Hong Li  9 ,  Roger E Stevenson  10 ,  Raymond J Louie  10 ,  Wallid Deb  3 ,  Erin Torti  11 ,  Virginie Vignard  12 ,  Kirsty McWalter  11 ,  F Lucy Raymond  13 ,  Farrah Rajabi  14 ,  Emmanuelle Ranza  15 ,  Detelina Grozeva  16 ,  Stephanie A Coury  14 ,  Xavier Blanc  15 ,  Elise Brischoux-Boucher  17 ,  Boris Keren  18 ,  Katrin Õunap  19 ,  Karit Reinson  19 ,  Pilvi Ilves  20 ,  Ingrid M Wentzensen  11 ,  Eileen E Barr  9 ,  Solveig Heide Guihard  21 ,  Perrine Charles  18 ,  Eleanor G Seaby  22 ,  Kristin G Monaghan  11 ,  Marlène Rio  23 ,  Yolande van Bever  24 ,  Marjon van Slegtenhorst  24 ,  Wendy K Chung  25 ,  Ashley Wilson  26 ,  Delphine Quinquis  27 ,  Flora Bréhéret  27 ,  Kyle Retterer  11 ,  Pierre Lindenbaum  12 ,  Emmanuel Scalais  28 ,  Lindsay Rhodes  11 ,  Katrien Stouffs  29 ,  Elaine M Pereira  26 ,  Sara M Berger  26 ,  Sarah S Milla  30 ,  Ankita B Jaykumar  31 ,  Melanie H Cobb  31 ,  Shreyas Panchagnula  4 ,  Phan Q Duy  8 ,  Marie Vincent  3 ,  Sandra Mercier  3 ,  Brigitte Gilbert-Dussardier  32 ,  Xavier Le Guillou  32 ,  Séverine Audebert-Bellanger  33 ,  Sylvie Odent  34 ,  Sébastien Schmitt  27 ,  Pierre Boisseau  27 ,  Dominique Bonneau  7 ,  Annick Toutain  35 ,  Estelle Colin  7 ,  Laurent Pasquier  34 ,  Richard Redon  12 ,  Arjan Bouman  24 ,  Jill A Rosenfeld  36 ,  Michael J Friez  10 ,  Helena Pérez-Peña  37 ,  Syed Raza Akhtar Rizvi  37 ,  Shozeb Haider  38 ,  Stylianos E Antonarakis  39 ,  Charles E Schwartz  10 ,  Francisco Martínez  4 ,  Stéphane Bézieau  3 ,  Kristopher T Kahle  40 ,  Bertrand Isidor  3
Affiliations
  • 1. Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France. Electronic address: [email protected].
  • 2. Hatherly Laboratories, The Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter, Exeter, United Kingdom; Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT; State Key Laboratory of Bio-Organic and Natural Products Chemistry, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3. Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
  • 4. Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
  • 5. Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT.
  • 6. Hatherly Laboratories, The Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter, Exeter, United Kingdom.
  • 7. Département de Biochimie et Génétique, Centre Hospitalier Universitaire Angers, Angers, France; UMR CNRS 6214, INSERM 1083, Université d'Angers, Angers, France.
  • 8. Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT.
  • 9. Departments of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA.
  • 10. Greenwood Genetic Center, Greenwood, SC.
  • 11. GeneDx, Gaithersburg, MD.
  • 12. Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
  • 13. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Biomedical Campus Cambridge, Cambridge, United Kingdom.
  • 14. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
  • 15. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
  • 16. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Biomedical Campus Cambridge, Cambridge, United Kingdom; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom.
  • 17. Centre de Génétique Humaine, CHU de Besançon, Université de Bourgogne Franche-Comté, Besançon, France.
  • 18. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 19. Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia.
  • 20. Department of Clinical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia; Department of Radiology, Tartu University Hospital, Tartu, Estonia.
  • 21. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Groupe de Recherche Clinique, Déficience Intellectuelle et Autisme, Sorbonne University, Paris, France.
  • 22. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Genomic Informatics Group, University of Southampton, Southampton, United Kingdom.
  • 23. Developmental Brain Disorders laboratory, INSERM UMR 1163, Imagine Institute, University of Paris, Paris, France; Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Necker Enfants Malades Hospital, APHP, Paris, France.
  • 24. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 25. Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, Columbia University New York, NY.
  • 26. Division of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY.
  • 27. Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
  • 28. Division of Pediatric Neurology, Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
  • 29. Neurogenetics Research Group, Reproduction and Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan, Brussels, Belgium.
  • 30. Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA.
  • 31. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX.
  • 32. Service de Génétique, CHU Poitiers, Poitiers, France.
  • 33. Génétique Médicale, CHRU Brest, Brest, France.
  • 34. Service de Génétique Clinique, ERN ITHACA, CHU Rennes, Rennes, France; Institut de Génétique et Développement de Rennes, IGDR UMR 6290 CNRS, INSERM, IGDR Univ Rennes, Rennes, France.
  • 35. Unité de Génétique Médicale, Centre Hospitalier Régional Universitaire de Tours, France; Unité Mixte de Recherche 1253, iBrain, Université de Tours, Institut National de la Santé et de la Recherche Médicale, Tours, France.
  • 36. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
  • 37. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, London, United Kingdom.
  • 38. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, London, United Kingdom; Centre for Advanced Research Computing, University College London, London, United Kingdom.
  • 39. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.
  • 40. Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT; Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT; NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine, Yale University, New Haven, CT; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT. Electronic address: [email protected].
PMID: 35678782 DOI: 10.1016/j.gim.2022.05.009
Abstract

Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.

Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).

Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of Epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.

Conclusion: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable Epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Keywords
Exome sequencing; KCC2; Neurodevelopmental disease; WNK3; X-linked intellectual disability.