Molecular Diagnostic and Phenotypic Findings in Individuals with SCN1A-Related Disease Identified Through a Sponsored, No-Charge Epilepsy Genetic Testing Program

Abstract number : 3.351
Submission category : 12. Genetics / 12A. Human Studies
Year : 2021
Submission ID : 1825951
Source : www.aesnet.org
Presentation date : 12/6/2021 12:00:00 PM
Published date : Nov 22, 2021, 12:51 PM

Authors :
Jennifer Gorzelany, - Encoded Therapeutics; Rosie O'Donnell - Encoded Therapeutics; Britt Johnson - Invitae; Ana Morales - Invitae; David Lapidus - Invitae; Maria Candida Vila - Encoded Therapeutics; Salvador Rico - Encoded Therapeutics; Barry Ticho - Stoke Therapeutics; Emma James - Encoded Therapeutics

Rationale: Disease-causing variants in the SCN1A gene are associated with a spectrum of epilepsy disorders, ranging from generalized epilepsy with febrile seizures+ (GEFS+) to Dravet syndrome (DS). DS is a severe, early-onset developmental and epileptic encephalopathy characterized by frequent prolonged seizures, status epilepticus, and cognitive disability and behavioral difficulties. As precision medicine therapies emerge, rapid and early molecular diagnosis will enable early intervention. Here we report molecular diagnostic and phenotypic findings of 271 patients with pathogenic and likely pathogenic variants in SCN1A identified through a sponsored, no-charge, targeted epilepsy gene panel testing program for children suspected of having genetic epilepsy.

Methods: At testing, eligible participants had at least one unprovoked seizure and were either 0-48 months old (from Feb/2019 to Jan/2020) or 0-96 months old (Jan/2020 to May/2020). Ordering physicians completed a test requisition form with information about seizure phenotype(s), neurodevelopmental and treatment history. The sponsored testing program used a multi‐gene, next‐generation sequencing panel with simultaneous sequence and exonic copy number variant detection to investigate up to 186 epilepsy-related genes.

Results: Of 15,162 patients tested, 271 (1.8%) had a molecular diagnosis related to the SCN1A gene. For individuals with SCN1A-related disease the mean age at molecular diagnosis was 26.4 months and at first seizure was 12.5 months. The most common variant types were missense (49.8%), nonsense (23.2%), frameshift (12.5%) and splice variants (4.8%). Consistent with prior reports, truncating variant types were associated with earlier age at seizure onset (7.94 vs. 16 months). In the 6 months prior to testing,
92% of patients < 1 year experienced 1 or more prolonged seizures ( >5 minutes) and 52% of patients 1-< 2 years old experienced 4 or more prolonged seizures. The prevalence of developmental delay generally increased with age.

Conclusions: Although the clinical information in our dataset represents a single point in time, the trends identified are consistent with the known natural course of DS. Through the sponsored, no-charge gene panel testing program, a large cohort of individuals with SCN1A-related disease has been identified, 60% of whom received a genetic diagnosis prior to 2 years of age. As precision medicine therapies emerge, accurate and timely identification of SCN1A disease-causing variants will enable early intervention and optimal treatment.

Funding: Please list any funding that was received in support of this abstract.: This abstract was supported by Encoded Therapeutics.

Categories : Genetics
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