The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures
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Objective: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype–phenotype correlations of a large EIMFS cohort. Methods: Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results: We ascertained 135 patients from 128 unrelated families. Ninety‐three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1 , ATP1A3 ; X‐linked CDKL5 , PIGA ; and recessive ITPA , AIMP1 , KARS , WWOX . The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands ( SCN2A , GABRB3 ) and 3 unaffected mothers ( KCNT1 ). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A , KCNQ2 , and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation: We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821–831
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The genes that cause EIMFS may follow autosomal dominant, X-linked and autosomal recessive inheritance, so an understanding of how each gene is inherited is essential when providing accurate diagnostic and genetic counselling for families.
“The genes that cause EIMFS may follow autosomal dominant, X-linked and autosomal recessive inheritance, so an understanding of how each gene is inherited is essential when providing accurate diagnostic and genetic counselling for families 168 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [168]
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- Authors
- Burgess, R., Wang, S., McTague, A., Boysen, K. E., Yang, X., Zeng, Q., Myers, K. A., Rochtus, A., Trivisano, M., Gill, D., EIMFS Consortium, Sadleir, L. G., Specchio, N., Guerrini, R., Marini, C., Zhang, Y., Mefford, H. C., Kurian, M. A., Poduri, A. H., & Scheffer, I. E.
- Affiliations
- The University of Melbourne (AU)
- University College London (GB)
- Peking University First Hospital (CN)
- Boston Children's Hospital (US)
- Bambino Gesù Children's Hospital (IT)
- Children's Hospital at Westmead (AU)
- University of Otago (NZ)
- Meyer Children's Hospital (IT)
- University of Washington (US)
- National Health Service (GB)
- Royal Children's Hospital (AU)
- Corresponding author
- Scheffer, Ingrid E.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2019-11-19
- Volume
- 86
- Issue
- 6
- Pages
- 821-831
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC7423163
- OpenAlex
- W2980781784
- Cited by
- 141
- References
- 49
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 13 · 2023: 22 · 2022: 22 · 2021: 30 · 2020: 20 · 2019: 2
- FWCI
- 14.74
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-02-25)
- Open access
- bronze
- doi.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Belgian American Educational Foundation
- Bureau of Educational and Cultural Affairs
- National Health and Medical Research Council (1006110, 1091593, 1104831, 628952)
- National Institutes of Health (NINDS NS069605)
- Seventh Framework Programme (602531)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- epilepsy of infancy with migrating focal seizures, genetic factors, genotype-phenotype correlation, KCNT1, SCN2A, KCNQ2, KCNQ3, KC
- MeSH terms
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Seizures, Spasms, Infantile, Cohort Studies, Genetic Predisposition to Disease
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