<scp><i>SCN1A</i></scp> pathogenic variants do not have a distinctive blood‐derived <scp>DNA</scp> methylation signature

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.

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Publication Details

Journal
Epilepsia
Published
2025-02-11
DOI
https://doi.org/10.1111/epi.18315
Citations
2
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
3.63

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article

SCN1A pathogenic variants do not have a distinctive blood‐derived DNA methylation signature

Lynette G. Sadleir, Andreas Brunklaus, Heather C. Mefford, Ingrid Eileen Scheffer et al.
2 citations
Epilepsia
Genomics and Rare Diseases
3.63
article

SCN1A pathogenic variants do not have a distinctive blood‐derived DNA methylation signature

Lynette G. Sadleir, Andreas Brunklaus, Heather C. Mefford, Ingrid Eileen Scheffer, Gaëtan Lesca, Christy W. LaFlamme, Daniel Stobo, Amy Schneider, Sophie Russ-Hall, Bekim Sadiković, Edith P. Almanza Fuerte, Joseph D. Symonds, Cassandra Rastin, Karim Karimi, Talia Allan
article en
2 citations

Abstract

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.

EpilepsiaVol. 66(4)
Université Claude Bernard Lyon 1 (FR), Western University (CA), Centre National de la Recherche Scientifique (FR), St. Jude Children's Research Hospital (US), Royal Children's Hospital (AU), Inserm (FR), The University of Melbourne (AU), Lyon College (US), Florey Institute of Neuroscience and Mental Health (AU), Royal Hospital for Children (GB), London Health Sciences Centre (CA), Hospices Civils de Lyon (FR), Murdoch Children's Research Institute (AU), Queen Elizabeth University Hospital (GB), Austin Health (AU), University of Glasgow (GB), University of Otago (NZ)
American Epilepsy Society, Citizens United for Research in Epilepsy, Cure Kids, Epilepsiatutkimussäätiö, Epilepsy Society, Medical Research Council, National Health and Medical Research Council, Health Research Council of New Zealand
Life in Land
Openalex Percentile: Top 9%
Genomics and Rare Diseases
3.63
DOIOpen Access PDFOpenAlex
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