Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Genet Med. 2022 Sep;24(9):1941-1951. doi: 10.1016/j.gim.2022.05.009. Epub 2022 Jun 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / abnormalities
  • Catalytic Domain / genetics
  • Hemizygote
  • Humans
  • Loss of Function Mutation
  • Male
  • Maternal Inheritance / genetics
  • Mental Retardation, X-Linked* / genetics
  • Mutation, Missense
  • Phosphorylation
  • Protein Serine-Threonine Kinases* / chemistry
  • Protein Serine-Threonine Kinases* / genetics
  • Symporters* / metabolism


  • SLC12A5 protein, human
  • Symporters
  • Protein Serine-Threonine Kinases
  • WNK3 protein, human