{Reference Type}: Journal Article
{Title}: Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
{Author}: 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;
{Journal}: Genet Med
{Volume}: 24
{Issue}: 9
{Year}: 09 2022
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2022.05.009
{Abstract}: 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.<BR>We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).<BR>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.<BR>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.