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Abstracts

Variants in ATP6V0C Causes a Dravet-like Developmental and Epileptic Encephalopathy

Abstract number : 2.047
Submission category : 12. Genetics / 12A. Human Studies
Year : 2024
Submission ID : 909
Source : www.aesnet.org
Presentation date : 12/8/2024 12:00:00 AM
Published date :

Authors :
Marlene Rong, MSc – Adult Genetic Epilepsy (AGE) Program, Toronto Western Hospital, University Health Network
Paula Marques, MD, CSCN (EEG) – Adult Genetic Epilepsy (AGE) Program, Toronto Western Hospital, University Health Network
Presenting Author: Quratulain Zulfiqar Ali, MD – Adult Genetic Epilepsy (AGE) Program, Toronto Western Hospital, University Health Network/University of Toronto

Ricardo Morcos, MD – Epilepsy and Neurogenetics Unit, Vithas Madrid University Hospitals, Madrid, Spain
Ilakkiah Chandran, MSc Candidate – Adult Genetic Epilepsy (AGE) Program, Toronto Western Hospital, University Health Network
Farah Qaiser, MSc – Adult Genetic Epilepsy (AGE) Program, Toronto Western Hospital, University Health Network
Rikke Møller, MD – Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre
Allan Bayat, MD, PhD – Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Filadelfia, Dianalund, Denmark
Guido Rubboli, MD – Danish Epilepsy Center, member of the European Reference Center EpiCARE; University of Copenhagen, Copenhagen, Denmark
Elena Gardella, MD, PhD – Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark
Miriam Reuter, MD – The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Tristan Sands, MD, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Annapurna Poduri, MD, MPH – Boston Children's Hospital
Elaine Wirrell, MD – Mayo Clinic
Rima Nabbout, MD, PhD – Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
Kette Valente, MD, PhD – University of Sao Paulo (USP)
Stéphane Auvin, MD, PhD, FAES – Paris-Cité University & Robert-Debré University Hospital, Paris, France
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
Andreas Brunklaus, MD – Royal Hospital for Children
Ángel Aledo-Serrano, MD, PhD – Epilepsy and Neurogenetics Unit, Vithas Madrid La Milagrosa University Hospital, Madrid, Spain Neurology Department, Ruber Internacional Hospital, Madrid, Spain
Danielle Andrade, MD, MSc, CSCN (EEG) – Adult Genetic Epilepsy (AGE) Program, University of Toronto, Toronto Western Hospital, University Health Network

Rationale: ·Dravet Syndrome (DS) is a developmental and epileptic encephalopathy (DEE).

·Diagnosis is clinical, but approximately 90% of patients have pathogenic variants in SCN1A.

· The ATP6V0C protein is highly expressed in the brain across the whole lifespan, and plays a key role in proton gradient generation and pH regulation.

·ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay.

Only 4 four adults (i.e., adults over 18 years of age) with ATP6V0C variants have been described in the literature thus far. Here, we describe 2 adult patients with a clinical diagnosis of DS caused by ATP6V0C variants.


Methods: Patients with DEEs were evaluated by physicians with expertise in managing DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS, but without known genetic causes, were evaluated through gene panels, whole exome sequencing and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews as well as interviews and physical examinations

Results: Out of 753 patients with DS, two unrelated individuals with classic DS features during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G >C, p.Gly107Arg) and (c.284C >T, p.Ala95Val), respectively. Both variants were absent in the general population and computational prediction algorithms suggested deleterious effects on protein structure and/or function (Table 1). No disease-causing variants in other genes previously associated with DS were found.


Conclusions: Here we describe two adult patients with Dravet-like syndrome and pathogenic/likely-pathogenic variants in ATP6V0C. We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet-like phenotype. This is relevant as these patients would not qualify for disease modifying anti-sense oligonucleotides (ASOs) or gene therapies targeting SCN1A.


Funding: None

Genetics