Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Sébastien Küry¹, Jinwei Zhang², Thomas Besnard³, Alfonso Caro-Llopis⁴, Xue Zeng⁵, Stephanie M Robert⁵, Sunday S Josiah⁶, Emre Kiziltug⁵, Anne-Sophie Denommé-Pichon⁷, Benjamin Cogné³, Adam J Kundishora⁸, Le T Hao⁸, Hong Li⁹, Roger E Stevenson¹⁰, Raymond J Louie¹⁰, Wallid Deb³, Erin Torti¹¹, Virginie Vignard¹², Kirsty McWalter¹¹, F Lucy Raymond¹³, Farrah Rajabi¹⁴, Emmanuelle Ranza¹⁵, Detelina Grozeva¹⁶, Stephanie A Coury¹⁴, Xavier Blanc¹⁵, Elise Brischoux-Boucher¹⁷, Boris Keren¹⁸, Katrin Õunap¹⁹, Karit Reinson¹⁹, Pilvi Ilves²⁰, Ingrid M Wentzensen¹¹, Eileen E Barr⁹, Solveig Heide Guihard²¹, Perrine Charles¹⁸, Eleanor G Seaby²², Kristin G Monaghan¹¹, Marlène Rio²³, Yolande van Bever²⁴, Marjon van Slegtenhorst²⁴, Wendy K Chung²⁵, Ashley Wilson²⁶, Delphine Quinquis²⁷, Flora Bréhéret²⁷, Kyle Retterer¹¹, Pierre Lindenbaum¹², Emmanuel Scalais²⁸, Lindsay Rhodes¹¹, Katrien Stouffs²⁹, Elaine M Pereira²⁶, Sara M Berger²⁶, Sarah S Milla³⁰, Ankita B Jaykumar³¹, Melanie H Cobb³¹, Shreyas Panchagnula⁴, Phan Q Duy⁸, Marie Vincent³, Sandra Mercier³, Brigitte Gilbert-Dussardier³², Xavier Le Guillou³², Séverine Audebert-Bellanger³³, Sylvie Odent³⁴, Sébastien Schmitt²⁷, Pierre Boisseau²⁷, Dominique Bonneau⁷, Annick Toutain³⁵, Estelle Colin⁷, Laurent Pasquier³⁴, Richard Redon¹², Arjan Bouman²⁴, Jill A Rosenfeld³⁶, Michael J Friez¹⁰, Helena Pérez-Peña³⁷, Syed Raza Akhtar Rizvi³⁷, Shozeb Haider³⁸, Stylianos E Antonarakis³⁹, Charles E Schwartz¹⁰, Francisco Martínez⁴, Stéphane Bézieau³, Kristopher T Kahle⁴⁰, Bertrand Isidor³

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: sebastien.kury@chu-nantes.fr.
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: kahle.kristopher@mgh.harvard.edu.

PMID: 35678782
DOI: 10.1016/j.gim.2022.05.009

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Sébastien Küry et al. Genet Med. 2022 Sep.

. 2022 Sep;24(9):1941-1951.

doi: 10.1016/j.gim.2022.05.009. Epub 2022 Jun 9.

Authors

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: sebastien.kury@chu-nantes.fr.
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: kahle.kristopher@mgh.harvard.edu.

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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Conflict of interest statement

Conflict of Interest E.T., K.M., K.R., I.M.W., K.G.M., and L.R. are employees of GeneDx, LLC. K.R. is a shareholder of OPKO Health, Inc. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. All other authors declare no conflicts of interest.

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Rare pathogenic variants in WNK3 cause X-linked intellectual disability

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Rare pathogenic variants in WNK3 cause X-linked intellectual disability

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