Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies

Declan Gallagher^{1

2}, Eduardo Pérez-Palma^{3

4}, Tobias Bruenger⁴, Ismael Ghanty^{1

2}, Eva Brilstra⁵, Berten Ceulemans⁶, Nicole Chemaly⁷, Iris de Lange⁵, Christel Depienne⁸, Renzo Guerrini⁹, Davide Mei⁹, Rikke S Møller^{10

11}, Rima Nabbout⁷, Brigid M Regan¹², Amy L Schneider¹², Ingrid E Scheffer^{12

13}, An-Sofie Schoonjans⁶, Joseph D Symonds^{1

2}, Sarah Weckhuysen^{14

15

16}, Sameer M Zuberi^{1

2}, Dennis Lal^{4

17

18

19}, Andreas Brunklaus^{1

2}

Affiliations

¹ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
² Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
³ Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago, Chile.
⁴ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁵ Department of Genetics, University Medical Center, Utrecht, the Netherlands.
⁶ Department of Child Neurology, University Hospital Antwerp, Antwerp, Belgium.
⁷ Reference Center for Rare Epilepsies, Department of Pediatric Neurology, Hôpital Necker-Enfants Malades, Université de Paris, Paris, France.
⁸ Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁹ Neuroscience Department, Children's Hospital A. Meyer Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) and University of Florence, Florence, Italy.
¹⁰ Danish Epilepsy Center, Filadelfia, Dianalund, Denmark.
¹¹ Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
¹² Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
¹³ University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia.
¹⁴ Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.
¹⁵ Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
¹⁶ Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
¹⁷ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁸ Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁹ Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, Texas, USA.

PMID: 38410936
DOI: 10.1111/epi.17882

Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies

Declan Gallagher et al. Epilepsia. 2024 Apr.

. 2024 Apr;65(4):1046-1059.

doi: 10.1111/epi.17882. Epub 2024 Feb 27.

Authors

Affiliations

¹ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
² Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
³ Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago, Chile.
⁴ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁵ Department of Genetics, University Medical Center, Utrecht, the Netherlands.
⁶ Department of Child Neurology, University Hospital Antwerp, Antwerp, Belgium.
⁷ Reference Center for Rare Epilepsies, Department of Pediatric Neurology, Hôpital Necker-Enfants Malades, Université de Paris, Paris, France.
⁸ Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁹ Neuroscience Department, Children's Hospital A. Meyer Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) and University of Florence, Florence, Italy.
¹⁰ Danish Epilepsy Center, Filadelfia, Dianalund, Denmark.
¹¹ Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
¹² Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
¹³ University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia.
¹⁴ Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.
¹⁵ Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
¹⁶ Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
¹⁷ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁸ Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁹ Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, Texas, USA.

PMID: 38410936
DOI: 10.1111/epi.17882

Abstract

Objective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood.

Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype.

Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ² = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS.

Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

Keywords: SCN1A; Dravet syndrome; GEFS+; genotype–phenotype associations; severe myoclonic epilepsy of infancy.

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Comment in

From All to One: Can a Large Cohort of Individuals with SCN1A-Related Epilepsy Offer Predictions for Other Individuals With SCN1A Variants?
Gerard EE. Gerard EE. Epilepsy Curr. 2025 Apr 30;25(3):158-160. doi: 10.1177/15357597251333279. eCollection 2025 May-Jun. Epilepsy Curr. 2025. PMID: 40322483 Free PMC article. No abstract available.

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Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies

Affiliations

Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies

Authors

Affiliations

Abstract

Comment in

References

REFERENCES

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical