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Variants in ATP6V0C are associated with Dravet-like developmental and epileptic encephalopathy
Marlene Rong1, Paula T Marques1, Quratulain Zulfiqar Ali1
1Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
Epilepsia
|March 14, 2025
Summary
Dravet syndrome (DS) can be associated with variants in ATP6V0C, not just SCN1A. This finding expands genetic understanding of severe epilepsy and developmental disorders.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy.
- While SCN1A gene variants cause ~90% of DS cases, other genes are being investigated.
- ATP6V0C has emerged as a potential candidate gene for epilepsy with or without developmental delay.
Purpose of the Study:
- To investigate the role of ATP6V0C variants in patients with a clinical diagnosis of Dravet syndrome.
- To identify novel genetic causes of Dravet syndrome beyond SCN1A.
Main Methods:
- Clinical evaluation of patients with developmental and epileptic encephalopathies by DS experts.
- Genetic analysis including gene panels, whole exome sequencing, and chromosome microarray for DS patients without known genetic causes.
- Phenotypic determination through comprehensive chart reviews, interviews, and physical examinations.
Main Results:
- Two unrelated adult patients with classic Dravet syndrome features were identified with de novo heterozygous missense variants in ATP6V0C.
- The identified ATP6V0C variants (p.(Gly107Arg) and p.(Ala95Val)) were absent in the general population and predicted to be deleterious.
- No pathogenic variants in other known DS-associated genes were found in these patients.
Conclusions:
- Pathogenic variants in ATP6V0C are associated with a Dravet-like phenotype in severe cases.
- This expands the genetic landscape of Dravet syndrome and related disorders.
- Identifying ATP6V0C variants is crucial as these patients may not be candidates for SCN1A-targeted therapies.
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