Rare pathogenic variants in WNK3 cause X-linked intellectual disability

• DOI: 10.1016/j.gim.2022.05.009
• Publication Date: 2022-06-10T00:04:33Z
• Authors: Sébastien Küry; Jinwei Zhang; Thomas Besnard; Alfonso Caro-Llopis; Xue Zeng; Stephanie M. Robert; Sunday S. Josiah; Emre Kiziltug; Anne-Sophie Denom...; Benjamin Cogné; Adam J. Kundishora; Le T. Hao; Hong Li; Roger E. Stevenson; Raymond J. Louie; Wallid Deb; Erin Torti; Virginie Vignard; Kirsty McWalter; F. Lucy Raymond; Farrah Rajabi; Emmanuelle Ranza; Detelina Grozeva; Stephanie A. Coury; Xavier Blanc; Elise Brischoux-B...; Boris Keren; Katrin Õunap; Karit Reinson; Pilvi Ilves; Ingrid M. Wentzensen; Eileen E. Barr; Solveig Heide Gui...; Perrine Charles; Eleanor G. Seaby; Kristin G. Monaghan; Marlène Rio; Yolande van Bever; Marjon van Slegte...; Wendy K. Chung; Ashley Wilson; Delphine Quinquis; Flora Bréhéret; Kyle Retterer; Pierre Lindenbaum; Emmanuel Scalais; Lindsay Rhodes; Katrien Stouffs; Elaine M. Pereira; Sara M. Berger; Sarah S. Milla; Ankita B. Jaykumar; Melanie H. Cobb; Shreyas Panchagnula; Phan Q. Duy; Marie Vincent; Sandra Mercier; Brigitte Gilbert-...; Xavier Le Guillou; Séverine Audebert...; Sylvie Odent; Sébastien Schmitt; Pierre Boisseau; Dominique Bonneau; Annick Toutain; Estelle Colin; Laurent Pasquier; Richard Redon; Arjan Bouman; Jill. A. Rosenfeld; Michael J. Friez; Helena Pérez-Peña; Syed Raza Akhtar ...; Shozeb Haider; Stylianos E. Anto...; Charles E. Schwartz; Francisco Martínez; Stéphane Bézieau; Kristopher T. Kahle; Bertrand Isidor
• Keywords: MESH: Symporters; Exome sequencing; Male; MESH: Mutation; KCC2; Mutation, Missense; 610; MESH: Catalytic Domain; Neurodevelopmental disease; [SDV.GEN] Life Sciences [q-bio]/Genetics; Protein Serine-Threonine Kinases; 576; X-linked intellectual disability; MESH: Brain; 03 medical and health sciences; WNK3; SDG 3 - Good Health and Well-being; Loss of Function Mutation; MESH: Mental Retardation; Catalytic Domain; MESH: Mental Retardation, X-Linked; Humans; Phosphorylation; MESH: Hemizygote; Hemizygote; MESH: Mutation, Missense; [SDV.GEN]Life Sciences [q-bio]/Genetics; 0303 health sciences; MESH: Humans; MESH: Phosphorylation; Symporters; Brain; MESH: Loss of Function Mutation; X-Linked; MESH: Protein Serine-Threonine Kinases; MESH: Male; Mental Retardation, X-Linked; Maternal Inheritance; Missense; MESH: Maternal Inheritance

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