The phenotypic spectrum of KCNT1: a new family with variable epilepsy syndromes including mild focal epilepsy.

Background And Objective: Pathogenic variants in KCNT1 have been associated with severe forms of epilepsy, typically sleep-related hypermotor epilepsy or epilepsy of infancy with migrating focal seizures. To show that pathogenic variants in KCNT1 can be associated with mild extra-frontal epilepsy, we report a KCNT1 family with a wide spectrum of phenotypes ranging from developmental and epileptic encephalopathy to mild focal epilepsy without cognitive regression and not consistent with sleep-related hypermotor epilepsy.

Methods: A large Canadian family of Caucasian descent including 9 affected family members was recruited. Family members were phenotyped by direct interview and review of existing medical records. Clinical epilepsy gene panel analysis and exome sequencing were performed.

Results: Phenotypic information was available for five family members of which two had developmental and epileptic encephalopathy and three had normal development and focal epilepsy with presumed extra-frontal onset. All three had predominantly nocturnal seizures that did not show hyperkinetic features. All three reported clusters of seizures at night with a feeling of being unable to breathe associated with gasping for air, choking and/or repetitive swallowing possibly suggesting insular or opercular involvement. Genetic analysis identified a heterozygous KCNT1 c.2882G > A, p.Arg961His variant that was predicted to be deleterious.

Discussion: This family demonstrates that the phenotypic spectrum associated with KCNT1 pathogenic variants is broader than previously assumed. Our findings indicate that variants in KCNT1 can be associated with mild focal epilepsy and should not be excluded during variant interpretation in such patients based solely on gene-disease validity.