2025/02/11 by Christy W. LaFlamme, Karim Karimi, Cassandra Rastin +12 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · #Genomics and Rare Diseases #Epigenetics and DNA Methylation #Genomic variations and chromosomal abnormalities
paper · pdf · doi:10.1111/epi.18315
openalex publication_date 2025/02/11 · openalex created_date 2025/02/11 · openalex updated_date 2026/07/28
DNA methylation signatures ("episignatures") can be used as biomarkers of genetic aberrations, clinical phenotypes, and environmental exposures in rare diseases. Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures. However, whether SCN1A, the most prominent epilepsy gene, has one or more episignatures has not yet been determined. We generated genome-wide DNA methylation data and performed episignature analysis on 64 individuals with Dravet syndrome due to pathogenic loss-of-function (LOF) variants in SCN1A and seven individuals with early infantile SCN1A developmental and epileptic encephalopathy due to pathogenic gain-of-function (GOF) variants in SCN1A, relative to a large reference database of controls and rare disease episignature-positive cohorts. We analyzed all samples with LOF variants together and performed separate analyses for missense, nonsense, and GOF variant cohorts. A reproducible blood-derived episignature was not evident in any of the cohorts using current analytical approaches and reference data.