Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Küry, Sébastien, Zhang, Jinwei, Besnard, Thomas, Caro-Llopis, Alfonso, Zeng, Xue, Robert, Stephanie M., Josiah, Sunday S., Kiziltug, Emre, Denommé-Pichon, Anne-Sophie, Cogné, Benjamin, Kundishora, Adam J., Hao, Le T., Li, Hong, Stevenson, Roger E., Louie, Raymond J., Deb, Wallid, Torti, Erin, Vignard, Virginie, McWalter, Kirsty, Raymond, F. Lucy, Rajabi, Farrah, Ranza, Emmanuelle, Grozeva, Detelina ORCID: https://orcid.org/0000-0003-3239-8415, Coury, Stephanie A., Blanc, Xavier, Brischoux-Boucher, Elise, Keren, Boris, Õunap, Katrin, Reinson, Karit, Ilves, Pilvi, Wentzensen, Ingrid M., Barr, Eileen E., Guihard, Solveig Heide, Charles, Perrine, Seaby, Eleanor G., Monaghan, Kristin G., Rio, Marlène, van Bever, Yolande, van Slegtenhorst, Marjon, Chung, Wendy K., Wilson, Ashley, Quinquis, Delphine, Bréhéret, Flora, Retterer, Kyle, Lindenbaum, Pierre, Scalais, Emmanuel, Rhodes, Lindsay, Stouffs, Katrien, Pereira, Elaine M., Berger, Sara M., Milla, Sarah S., Jaykumar, Ankita B., Cobb, Melanie H., Panchagnula, Shreyas, Duy, Phan Q., Vincent, Marie, Mercier, Sandra, Gilbert-Dussardier, Brigitte, Le Guillou, Xavier, Audebert-Bellanger, Séverine, Odent, Sylvie, Schmitt, Sébastien, Boisseau, Pierre, Bonneau, Dominique, Toutain, Annick, Colin, Estelle, Pasquier, Laurent, Redon, Richard, Bouman, Arjan, Rosenfeld, Jill. A., Friez, Michael J., Pérez-Peña, Helena, Akhtar Rizvi, Syed Raza, Haider, Shozeb, Antonarakis, Stylianos E., Schwartz, Charles E., Martínez, Francisco, Bézieau, Stéphane, Kahle, Kristopher T. and Isidor, Bertrand 2022. Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics in Medicine 24 (9) , pp. 1941-1951. 10.1016/j.gim.2022.05.009

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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 identifier 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 identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Additional Information:	License information from Publisher: LICENSE 1: Title: This article is under embargo with an end date yet to be finalised.
Publisher:	American College of Medical Genetics and Genomics
ISSN:	1098-3600
Date of Acceptance:	11 May 2022
Last Modified:	19 Oct 2022 12:39
URI:	https://orca.cardiff.ac.uk/id/eprint/150469

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