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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• KCNT2 gene variants are associated with epileptic encephalopathy and specific facial features.
• Previous research linked KCNT2 mutations to severe neurological conditions.

Observation:

• Two individuals presented with intellectual disability, dysmorphic features, hypertrichosis, and macrocephaly.
• Both individuals carried de novo KCNT2 missense variants at the Arg190 residue, previously associated with epilepsy.

Findings:

• Neither patient exhibited epilepsy, challenging the established phenotype.
• Homology modeling suggests these variants likely cause a constitutively open KCNT2 channel state.
• This is the first report of KCNT2 pathogenic variants leading to a developmental disorder without epilepsy.

Implications:

• Expands the clinical spectrum of KCNT2-related disorders.
• Highlights the importance of considering KCNT2 in developmental phenotypes beyond epilepsy.
• Provides insights into KCNT2 channel function and its role in neurodevelopment.