Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
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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, 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, Isidor Bertrand
Аннотация
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.