Novel KCNQ2 Variants Related to a Variable Phenotypic Spectrum Ranging from Epilepsy with Auditory Features to Severe Developmental and Epileptic Encephalopathies

Pathogenic <i>KCNQ2</i> variants are associated with neonatal epilepsies, ranging from self-limited neonatal epilepsy to <i>KCNQ2</i>-developmental and epileptic encephalopathy (DEE). In this study, next-generation sequencing was performed, applying a panel of 142 epilepsy genes on three unrelated individuals and affected family members, showing a wide variability in the epileptic spectrum. The genetic analysis revealed two likely pathogenic missense variants (c.1378G>A and c.2251T>G) and the already-reported pathogenic splice site (c.1631+1G>A) in <i>KCNQ2</i> (HGNC:6296). The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures. The gene panel contained further genes related to EAFs (<i>LGI1</i>, <i>RELN</i>, <i>SCN1A</i>, and <i>DEPDC5</i>), which were tested with negative results. The phenotypes observed in family 2 members, sharing the splice site variant, were neonatal seizures and focal epilepsy in childhood. The last unrelated proband, harboring the de novo missense c.1378G>A, presented a clinical phenotype consistent with DEE. In conclusion, we identified two unreported <i>KCNQ2</i> variants, and report a proband with EAFs and individuals without typical <i>KCNQ2</i> neonatal seizures. Our study underscores the extreme variability in the phenotypic spectrum of <i>KCNQ2</i>-related epilepsies and unveils the prospect of its inclusion in screening panels for EAFs.