Christina Cherian1, Juan P Appendino2, Setareh Ashtiani3, Paolo Federico1,4,5,6, Christine P Molnar5, Marina Kerr3,7, Aneal Khan3,7, Ping Yee Billie Au3,7, Karl Martin Klein8,9,10,11,12,13,14. 1. Department of Clinical Neurosciences, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, 1403 29 Street NW, Calgary, AB, T2N 2T9, Canada. 2. Division of Clinical Neuroscience, Department of Pediatrics, Cumming School of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada. 3. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 4. Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. 5. Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 6. Seaman Family MR Research Centre, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 7. Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada. 8. Department of Clinical Neurosciences, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, 1403 29 Street NW, Calgary, AB, T2N 2T9, Canada. karl.klein@ucalgary.ca. 9. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. karl.klein@ucalgary.ca. 10. Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. karl.klein@ucalgary.ca. 11. Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada. karl.klein@ucalgary.ca. 12. Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. karl.klein@ucalgary.ca. 13. Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University, Frankfurt, Germany. karl.klein@ucalgary.ca. 14. Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany. karl.klein@ucalgary.ca.
Abstract
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.
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.
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