Expanding the Phenotypic Spectrum of KCNT2-Related Encephalopathy: A Novel de Novo Stop-Gain Variant with Coffin–Siris–Like Features

Pathogenic variants in KCNT2 have recently been recognized as a rare cause of Developmental and Epileptic Encephalopathy (DEE-57), characterized by early-onset refractory seizures and severe neurodevelopmental impairment, with only a limited number of cases reported worldwide. We describe a 7-month-old female infant, born to non-consanguineous parents, who presented with recurrent afebrile seizures since the neonatal period, global developmental delay, failure to thrive, and microcephaly. Seizures began on day 6 of life and evolved into drug-resistant epilepsy with multifocal onset. On examination, the child exhibited dysmorphic features including cleft palate, hirsutism, thick eyebrows, long eyelashes, broad nasal tip, smooth philtrum, and spatulate fingers. Electroencephalography revealed multifocal epileptiform discharges with migrating seizure activity, while neuroimaging showed only minor birth-related hemorrhages. Whole exome sequencing identified a novel heterozygous nonsense variant in KCNT2 (c.2836A>T; p.Lys946Ter), consistent with developmental and epileptic encephalopathy-57. In addition, a variant of uncertain significance in ARID1A was detected, raising the possibility of phenotypic overlap with Coffin–Siris–like features. The child required multiple anti-seizure medications with only partial seizure control and persistent developmental delay. This case expands the genotypic and phenotypic spectrum of KCNT2-related encephalopathy and highlights a potential syndromic overlap, emphasizing the importance of comprehensive genetic evaluation in infants with early-onset refractory epilepsy.