2. Academic Validation
  3. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

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

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.

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