Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Sébastien Küry; Jinwei Zhang; Thomas Besnard; Alfonso Caro-Llopis; Xue Zeng; Stephanie M. Robert; Sunday S. Josiah; Emre Kiziltug; Anne Sophie Denommé-Pichon; 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-Boucher; Boris Keren; Katrin Õunap; Karit Reinson; Pilvi Ilves; Ingrid M. Wentzensen; Eileen E. Barr; Solveig Heide Guihard; Perrine Charles; Eleanor G. Seaby; Kristin G. Monaghan; Marlène Rio; Yolande van Bever; Marjon van Slegtenhorst; 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-Dussardier; Xavier Le Guillou; Séverine Audebert-Bellanger; 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 Rizvi; Shozeb Haider; Stylianos E. Antonarakis; Charles E. Schwartz; Francisco Martínez; Stéphane Bézieau; Kristopher T. Kahle; Bertrand Isidor

doi:10.1016/j.gim.2022.05.009

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne Sophie Denommé-Pichon, 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 RaymondFarrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, 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-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, 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 Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1941-1951
Number of pages	11
Journal	Genetics in Medicine
Volume	24
Issue number	9
DOIs	https://doi.org/10.1016/j.gim.2022.05.009
State	Published - Sep 2022

Keywords

Exome sequencing
KCC2
Neurodevelopmental disease
WNK3
X-linked intellectual disability

ASJC Scopus subject areas

Genetics(clinical)

Access to Document

10.1016/j.gim.2022.05.009

Cite this

Küry, S., Zhang, J., Besnard, T., Caro-Llopis, A., Zeng, X., Robert, S. M., Josiah, S. S., Kiziltug, E., Denommé-Pichon, A. S., Cogné, B., Kundishora, A. J., Hao, L. T., Li, H., Stevenson, R. E., Louie, R. J., Deb, W., Torti, E., Vignard, V., McWalter, K., ... Isidor, B. (2022). Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics in Medicine, 24(9), 1941-1951. https://doi.org/10.1016/j.gim.2022.05.009

Küry, S, Zhang, J, Besnard, T, Caro-Llopis, A, Zeng, X, Robert, SM, Josiah, SS, Kiziltug, E, Denommé-Pichon, AS, Cogné, B, Kundishora, AJ, Hao, LT, Li, H, Stevenson, RE, Louie, RJ, Deb, W, Torti, E, Vignard, V, McWalter, K, Raymond, FL, Rajabi, F, Ranza, E, Grozeva, D, Coury, SA, Blanc, X, Brischoux-Boucher, E, Keren, B, Õunap, K, Reinson, K, Ilves, P, Wentzensen, IM, Barr, EE, Guihard, SH, Charles, P, Seaby, EG, Monaghan, KG, Rio, M, van Bever, Y, van Slegtenhorst, M, Chung, WK, Wilson, A, Quinquis, D, Bréhéret, F, Retterer, K, Lindenbaum, P, Scalais, E, Rhodes, L, Stouffs, K, Pereira, EM, Berger, SM, Milla, SS, Jaykumar, AB, Cobb, MH, Panchagnula, S, Duy, PQ, Vincent, M, Mercier, S, Gilbert-Dussardier, B, Le Guillou, X, Audebert-Bellanger, S, Odent, S, Schmitt, S, Boisseau, P, Bonneau, D, Toutain, A, Colin, E, Pasquier, L, Redon, R, Bouman, A, Rosenfeld, JA, Friez, MJ, Pérez-Peña, H, Akhtar Rizvi, SR, Haider, S, Antonarakis, SE, Schwartz, CE, Martínez, F, Bézieau, S, Kahle, KT & Isidor, B 2022, 'Rare pathogenic variants in WNK3 cause X-linked intellectual disability', Genetics in Medicine, vol. 24, no. 9, pp. 1941-1951. https://doi.org/10.1016/j.gim.2022.05.009

@article{682ee4a6bc154beb87f4c3c851db77ee,

title = "Rare pathogenic variants in WNK3 cause X-linked intellectual disability",

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",

author = "S{\'e}bastien K{\"u}ry and Jinwei Zhang and Thomas Besnard and Alfonso Caro-Llopis and Xue Zeng and Robert, {Stephanie M.} and Josiah, {Sunday S.} and Emre Kiziltug and Denomm{\'e}-Pichon, {Anne Sophie} and Benjamin Cogn{\'e} and Kundishora, {Adam J.} and Hao, {Le T.} and Hong Li and Stevenson, {Roger E.} and Louie, {Raymond J.} and Wallid Deb and Erin Torti and Virginie Vignard and Kirsty McWalter and Raymond, {F. Lucy} and Farrah Rajabi and Emmanuelle Ranza and Detelina Grozeva and Coury, {Stephanie A.} and Xavier Blanc and Elise Brischoux-Boucher and Boris Keren and Katrin {\~O}unap and Karit Reinson and Pilvi Ilves and Wentzensen, {Ingrid M.} and Barr, {Eileen E.} and Guihard, {Solveig Heide} and Perrine Charles and Seaby, {Eleanor G.} and Monaghan, {Kristin G.} and Marl{\`e}ne Rio and {van Bever}, Yolande and {van Slegtenhorst}, Marjon and Chung, {Wendy K.} and Ashley Wilson and Delphine Quinquis and Flora Br{\'e}h{\'e}ret and Kyle Retterer and Pierre Lindenbaum and Emmanuel Scalais and Lindsay Rhodes and Katrien Stouffs and Pereira, {Elaine M.} and Berger, {Sara M.} and Milla, {Sarah S.} and Jaykumar, {Ankita B.} and Cobb, {Melanie H.} and Shreyas Panchagnula and Duy, {Phan Q.} and Marie Vincent and Sandra Mercier and Brigitte Gilbert-Dussardier and {Le Guillou}, Xavier and S{\'e}verine Audebert-Bellanger and Sylvie Odent and S{\'e}bastien Schmitt and Pierre Boisseau and Dominique Bonneau and Annick Toutain and Estelle Colin and Laurent Pasquier and Richard Redon and Arjan Bouman and Rosenfeld, {Jill A.} and Friez, {Michael J.} and Helena P{\'e}rez-Pe{\~n}a and {Akhtar Rizvi}, {Syed Raza} and Shozeb Haider and Antonarakis, {Stylianos E.} and Schwartz, {Charles E.} and Francisco Mart{\'i}nez and St{\'e}phane B{\'e}zieau and Kahle, {Kristopher T.} and Bertrand Isidor",

note = "Funding Information: We would like to thank all the participating families for participating in this study. This work was granted by the French network of University Hospitals HUGO (“H{\^o}pitaux Universitaires du Grand Ouest”); the French Ministry of Health; and the Health Regional Agencies from Poitou-Charentes (represented by Fr{\'e}d{\'e}rique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United States and the JPB Foundation, United States. This study is part of the GEM EXCELL, a network of excellence in genetics and genomics embedded in the French network of University Hospitals HUGO (“H{\^o}pitaux Universitaires du Grand Ouest”). This work was supported by the Estonian Research Council, Estonia grant PRG471 (K.{\~O}. and K.R.), the National Natural Science Foundation of China numbers. 81970238 and 82170406 (J.Z.), and The Royal Society UK, United Kingdom number IEC∖NSFC∖201094 (J.Z.). The Broad Institute Center for Mendelian Genomics, United States (UM1 HG008900) is funded by the National Human Genome Research Institute, United States with supplemental funding provided by the National Heart, Lung, and Blood Institute, United States under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute, United States. R.E.S. R.J.L. M.J.F. and C.E.S. were funded, in part, by a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN) and another grant from the National Institute of Neurological Disorders and Stroke, United States (NINDS; R01NS073854). Conceptualization: S.K. B.I. K.T.K. J.Z.; Data Curation: S.K. J.Z. T.B. A.C.-L. X.Z. S.M.R. S.S.J. E.K. A.-S.D.-P. B.C. A.J.K. L.T.H. H.L. R.E.S. R.J.L. W.D. E.T. V.V. K.M. F.L.R. F.R. E.R. D.G. S.A.C. X.B. E.B.-B. B.K. K.{\~O}. K.R. P.I. I.M.W. E.E.B. S.H.G. P.C. E.G.S. K.G.M. M.R. Y.v.B. M.v.S. W.K.C. A.W. D.Q. F.B. K.R. P.L. E.S. L.R. K.S. E.M.P. S.M.B. S.S.M, A.B.J. M.H.C. S.P. P.Q.D. M.V. S.M. B.G.-D. X.L.G. S.A.-B. S.O. S.S. P.B. D.B. A.T. E.C. L.P. R.R. A.B. J.A.R. M.J.F. H.P.-P. S.R.A.R. S.H. S.E.A. C.E.S. F.M. S.B. K.T.K. B.I.; Methodology: S.K. B.I. K.T.K. J.Z.; Writing-original draft: S.K. B.I. K.T.K. J.Z.; Writing-review and editing: S.K. J.Z. T.B. A.C.-L. X.Z. S.M.R. S.S.J. E.K. A.-S.D.-P. B.C. A.J.K. L.T.H. H.L. R.E.S. R.J.L. W.D. E.T. V.V. K.M. F.L.R. F.R. E.R. D.G. S.A.C. X.B. E.B.-B. B.K. K.{\~O}. K.R. P.I. I.M.W. E.E.B. S.H.G. P.C. E.G.S. K.G.M. M.R. Y.v.B. M.v.S. W.K.C. A.W. D.Q. F.B. K.R. P.L. E.S. L.R. K.S. E.M.P. S.M.B. S.S.M, A.B.J. M.H.C. S.P. P.Q.D. M.V. S.M. B.G.-D. X.L.G. S.A.-B. S.O. S.S. P.B. D.B. A.T. E.C. L.P. R.R. A.B. J.A.R. M.J.F. H.P.-P. S.R.A.R. S.H. S.E.A. C.E.S. F.M. S.B. K.T.K. B.I. Written informed consent was obtained for use of medical history, genetic testing report, and imaging (if applicable), as approved by the Institutional Review Board of the University Hospital Center (CHU) of Nantes. Allen Institute for Brain Science. BrainSpan. Accessed on May 10, 2022. www.brainspan.org, University of Washington, Hudson-Alpha Institute for Biotechnology, and Berlin Institute of Health. Combined Annotation Dependent Depletion (CADD). Accessed on May 10, 2022. https://cadd.gs.washington.edu/, National Center for Biotechnology Information. dbSNP. Accessed on May 10, 2022. http://www.ncbi.nlm.nih.gov/projects/SNP/, BHCMG Centers for Mendelian Genomics network. Accessed on May 10, 2022. GeneMatcher, https://genematcher.org/, Broad Institute of MIT and Harvard. GTEx portal. Accessed on May 10, 2022. https://gtexportal.org/home/gene/WNK3, Broad Institute of MIT and Harvard. gnomAD. Accessed on May 10, 2022. http://gnomad.broadinstitute.org/, Radboudumc. MetaDome. Accessed on May 10, 2022. https://stuart.radboudumc.nl/metadome/, The University of Melbourne. Missense Tolerance Ratio Gene Viewer. Accessed on May 10, 2022. http://mtr-viewer.mdhs.unimelb.edu.au/, Montpellier University Hospital. MobiDetails. Accessed on May 10, 2022. https://mobidetails.iurc.montp.inserm.fr/MD/, Johns Hopkins University. OMIM. Accessed on May 10, 2022. http://www.omim.org/, Rutgers University, University of California San Diego, University of California San Francisco, and San Diego Supercomputer Center. Protein Data Bank. Accessed on May 10, 2022. https://www.rcsb.org/ Funding Information: We would like to thank all the participating families for participating in this study. This work was granted by the French network of University Hospitals HUGO (“H{\^o}pitaux Universitaires du Grand Ouest”); the French Ministry of Health; and the Health Regional Agencies from Poitou-Charentes (represented by Fr{\'e}d{\'e}rique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United States and the JPB Foundation, United States . This study is part of the GEM EXCELL, a network of excellence in genetics and genomics embedded in the French network of University Hospitals HUGO (“H{\^o}pitaux Universitaires du Grand Ouest”). This work was supported by the Estonian Research Council, Estonia grant PRG471 (K.{\~O}. and K.R.), the National Natural Science Foundation of China numbers. 81970238 and 82170406 (J.Z.), and The Royal Society UK, United Kingdom number IEC∖NSFC∖201094 (J.Z.). The Broad Institute Center for Mendelian Genomics, United States (UM1 HG008900) is funded by the National Human Genome Research Institute, United States with supplemental funding provided by the National Heart, Lung, and Blood Institute, United States under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute, United States . R.E.S., R.J.L., M.J.F., and C.E.S. were funded, in part, by a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN) and another grant from the National Institute of Neurological Disorders and Stroke, United States (NINDS; R01NS073854). Publisher Copyright: {\textcopyright} 2022 American College of Medical Genetics and Genomics",

year = "2022",

month = sep,

doi = "10.1016/j.gim.2022.05.009",

language = "English (US)",

volume = "24",

pages = "1941--1951",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

TY - JOUR

T1 - Rare pathogenic variants in WNK3 cause X-linked intellectual disability

AU - Küry, Sébastien

AU - Zhang, Jinwei

AU - Besnard, Thomas

AU - Caro-Llopis, Alfonso

AU - Zeng, Xue

AU - Robert, Stephanie M.

AU - Josiah, Sunday S.

AU - Kiziltug, Emre

AU - Denommé-Pichon, Anne Sophie

AU - Cogné, Benjamin

AU - Kundishora, Adam J.

AU - Hao, Le T.

AU - Li, Hong

AU - Stevenson, Roger E.

AU - Louie, Raymond J.

AU - Deb, Wallid

AU - Torti, Erin

AU - Vignard, Virginie

AU - McWalter, Kirsty

AU - Raymond, F. Lucy

AU - Rajabi, Farrah

AU - Ranza, Emmanuelle

AU - Grozeva, Detelina

AU - Coury, Stephanie A.

AU - Blanc, Xavier

AU - Brischoux-Boucher, Elise

AU - Keren, Boris

AU - Õunap, Katrin

AU - Reinson, Karit

AU - Ilves, Pilvi

AU - Wentzensen, Ingrid M.

AU - Barr, Eileen E.

AU - Guihard, Solveig Heide

AU - Charles, Perrine

AU - Seaby, Eleanor G.

AU - Monaghan, Kristin G.

AU - Rio, Marlène

AU - van Bever, Yolande

AU - van Slegtenhorst, Marjon

AU - Chung, Wendy K.

AU - Wilson, Ashley

AU - Quinquis, Delphine

AU - Bréhéret, Flora

AU - Retterer, Kyle

AU - Lindenbaum, Pierre

AU - Scalais, Emmanuel

AU - Rhodes, Lindsay

AU - Stouffs, Katrien

AU - Pereira, Elaine M.

AU - Berger, Sara M.

AU - Milla, Sarah S.

AU - Jaykumar, Ankita B.

AU - Cobb, Melanie H.

AU - Panchagnula, Shreyas

AU - Duy, Phan Q.

AU - Vincent, Marie

AU - Mercier, Sandra

AU - Gilbert-Dussardier, Brigitte

AU - Le Guillou, Xavier

AU - Audebert-Bellanger, Séverine

AU - Odent, Sylvie

AU - Schmitt, Sébastien

AU - Boisseau, Pierre

AU - Bonneau, Dominique

AU - Toutain, Annick

AU - Colin, Estelle

AU - Pasquier, Laurent

AU - Redon, Richard

AU - Bouman, Arjan

AU - Rosenfeld, Jill A.

AU - Friez, Michael J.

AU - Pérez-Peña, Helena

AU - Akhtar Rizvi, Syed Raza

AU - Haider, Shozeb

AU - Antonarakis, Stylianos E.

AU - Schwartz, Charles E.

AU - Martínez, Francisco

AU - Bézieau, Stéphane

AU - Kahle, Kristopher T.

AU - Isidor, Bertrand

N1 - Funding Information: We would like to thank all the participating families for participating in this study. This work was granted by the French network of University Hospitals HUGO (“Hôpitaux Universitaires du Grand Ouest”); the French Ministry of Health; and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United States and the JPB Foundation, United States. This study is part of the GEM EXCELL, a network of excellence in genetics and genomics embedded in the French network of University Hospitals HUGO (“Hôpitaux Universitaires du Grand Ouest”). This work was supported by the Estonian Research Council, Estonia grant PRG471 (K.Õ. and K.R.), the National Natural Science Foundation of China numbers. 81970238 and 82170406 (J.Z.), and The Royal Society UK, United Kingdom number IEC∖NSFC∖201094 (J.Z.). The Broad Institute Center for Mendelian Genomics, United States (UM1 HG008900) is funded by the National Human Genome Research Institute, United States with supplemental funding provided by the National Heart, Lung, and Blood Institute, United States under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute, United States. R.E.S. R.J.L. M.J.F. and C.E.S. were funded, in part, by a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN) and another grant from the National Institute of Neurological Disorders and Stroke, United States (NINDS; R01NS073854). Conceptualization: S.K. B.I. K.T.K. J.Z.; Data Curation: S.K. J.Z. T.B. A.C.-L. X.Z. S.M.R. S.S.J. E.K. A.-S.D.-P. B.C. A.J.K. L.T.H. H.L. R.E.S. R.J.L. W.D. E.T. V.V. K.M. F.L.R. F.R. E.R. D.G. S.A.C. X.B. E.B.-B. B.K. K.Õ. K.R. P.I. I.M.W. E.E.B. S.H.G. P.C. E.G.S. K.G.M. M.R. Y.v.B. M.v.S. W.K.C. A.W. D.Q. F.B. K.R. P.L. E.S. L.R. K.S. E.M.P. S.M.B. S.S.M, A.B.J. M.H.C. S.P. P.Q.D. M.V. S.M. B.G.-D. X.L.G. S.A.-B. S.O. S.S. P.B. D.B. A.T. E.C. L.P. R.R. A.B. J.A.R. M.J.F. H.P.-P. S.R.A.R. S.H. S.E.A. C.E.S. F.M. S.B. K.T.K. B.I.; Methodology: S.K. B.I. K.T.K. J.Z.; Writing-original draft: S.K. B.I. K.T.K. J.Z.; Writing-review and editing: S.K. J.Z. T.B. A.C.-L. X.Z. S.M.R. S.S.J. E.K. A.-S.D.-P. B.C. A.J.K. L.T.H. H.L. R.E.S. R.J.L. W.D. E.T. V.V. K.M. F.L.R. F.R. E.R. D.G. S.A.C. X.B. E.B.-B. B.K. K.Õ. K.R. P.I. I.M.W. E.E.B. S.H.G. P.C. E.G.S. K.G.M. M.R. Y.v.B. M.v.S. W.K.C. A.W. D.Q. F.B. K.R. P.L. E.S. L.R. K.S. E.M.P. S.M.B. S.S.M, A.B.J. M.H.C. S.P. P.Q.D. M.V. S.M. B.G.-D. X.L.G. S.A.-B. S.O. S.S. P.B. D.B. A.T. E.C. L.P. R.R. A.B. J.A.R. M.J.F. H.P.-P. S.R.A.R. S.H. S.E.A. C.E.S. F.M. S.B. K.T.K. B.I. Written informed consent was obtained for use of medical history, genetic testing report, and imaging (if applicable), as approved by the Institutional Review Board of the University Hospital Center (CHU) of Nantes. Allen Institute for Brain Science. BrainSpan. Accessed on May 10, 2022. www.brainspan.org, University of Washington, Hudson-Alpha Institute for Biotechnology, and Berlin Institute of Health. Combined Annotation Dependent Depletion (CADD). Accessed on May 10, 2022. https://cadd.gs.washington.edu/, National Center for Biotechnology Information. dbSNP. Accessed on May 10, 2022. http://www.ncbi.nlm.nih.gov/projects/SNP/, BHCMG Centers for Mendelian Genomics network. Accessed on May 10, 2022. GeneMatcher, https://genematcher.org/, Broad Institute of MIT and Harvard. GTEx portal. Accessed on May 10, 2022. https://gtexportal.org/home/gene/WNK3, Broad Institute of MIT and Harvard. gnomAD. Accessed on May 10, 2022. http://gnomad.broadinstitute.org/, Radboudumc. MetaDome. Accessed on May 10, 2022. https://stuart.radboudumc.nl/metadome/, The University of Melbourne. Missense Tolerance Ratio Gene Viewer. Accessed on May 10, 2022. http://mtr-viewer.mdhs.unimelb.edu.au/, Montpellier University Hospital. MobiDetails. Accessed on May 10, 2022. https://mobidetails.iurc.montp.inserm.fr/MD/, Johns Hopkins University. OMIM. Accessed on May 10, 2022. http://www.omim.org/, Rutgers University, University of California San Diego, University of California San Francisco, and San Diego Supercomputer Center. Protein Data Bank. Accessed on May 10, 2022. https://www.rcsb.org/ Funding Information: We would like to thank all the participating families for participating in this study. This work was granted by the French network of University Hospitals HUGO (“Hôpitaux Universitaires du Grand Ouest”); the French Ministry of Health; and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United States and the JPB Foundation, United States . This study is part of the GEM EXCELL, a network of excellence in genetics and genomics embedded in the French network of University Hospitals HUGO (“Hôpitaux Universitaires du Grand Ouest”). This work was supported by the Estonian Research Council, Estonia grant PRG471 (K.Õ. and K.R.), the National Natural Science Foundation of China numbers. 81970238 and 82170406 (J.Z.), and The Royal Society UK, United Kingdom number IEC∖NSFC∖201094 (J.Z.). The Broad Institute Center for Mendelian Genomics, United States (UM1 HG008900) is funded by the National Human Genome Research Institute, United States with supplemental funding provided by the National Heart, Lung, and Blood Institute, United States under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute, United States . R.E.S., R.J.L., M.J.F., and C.E.S. were funded, in part, by a grant from the South Carolina Department of Disabilities and Special Needs (SCDDSN) and another grant from the National Institute of Neurological Disorders and Stroke, United States (NINDS; R01NS073854). Publisher Copyright: © 2022 American College of Medical Genetics and Genomics

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Exome sequencing

KW - KCC2

KW - Neurodevelopmental disease

KW - WNK3

KW - X-linked intellectual disability

UR - http://www.scopus.com/inward/record.url?scp=85131808629&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85131808629&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2022.05.009

DO - 10.1016/j.gim.2022.05.009

M3 - Article

C2 - 35678782

AN - SCOPUS:85131808629

SN - 1098-3600

VL - 24

SP - 1941

EP - 1951

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

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