• Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

      Jackson, Adam; orcid: 0000-0002-3674-3960; email: adam.jackson-5@postgrad.manchester.ac.uk; Banka, Siddharth; orcid: 0000-0002-8527-2210; Stewart, Helen; orcid: 0000-0002-1196-3000; Genomics England Research Consortium; Robinson, Hannah; Lovell, Simon; Clayton‐Smith, Jill (John Wiley & Sons, Inc., 2021-06-01)
      Abstract: KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.