Neurodevelopmental features in KCNQ2 developmental and epileptic encephalopathy may have limited associations with...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• KCNQ2 gene variants are linked to developmental and epileptic encephalopathy (DEE).
• The severity of DEE varies significantly among affected individuals.
• Understanding the genotype-phenotype correlation is crucial for predicting disease trajectory.

Purpose of the Study:

• To investigate the relationship between KCNQ2 variant dysfunction and the neurodevelopmental phenotype in KCNQ2-DEE.
• To analyze the impact of different variant functional classifications on clinical severity.
• To identify factors contributing to the variability in KCNQ2-DEE.

Main Methods:

• A parent-reported survey collected clinical and genetic data from individuals with KCNQ2-DEE.
• A composite non-seizure phenotype severity score (PSS) was developed for six key features.
• KCNQ2 variant function was assessed using voltage-clamp recordings and classified as severe loss of function (SLOF), loss of function (LOF), wild-type-like (WTL), or gain of function (GOF).

Main Results:

• 48 individuals with 38 unique KCNQ2 variants were included.
• The phenotype severity score (PSS) was higher in individuals with SLOF variants compared to LOF variants (p=0.02).
• A lower prevalence of epileptic spasms was observed in individuals with dominant-negative variants among those with SLOF or LOF variants.

Conclusions:

• Multiple and severe neurodevelopmental impairments are common in KCNQ2-DEE.
• KCNQ2 channel dysfunction shows a modest correlation with overall non-seizure phenotype severity.
• Factors beyond channel dysfunction likely contribute to the variable clinical severity observed in KCNQ2-DEE.