Abstract
Purpose: Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this etiology is buried under the burden of infections and perinatal insults in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs) are most severely affected by this diagnostic gap in Africa, because the rate of actionable findings is highest in DEE-associated genes. Methods: We tested 234 genetically naive South African children diagnosed with/possible DEE using gene panels, exome sequencing, and chromosomal microarray. Statistical comparison of electroclinical features in children with and children without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results: Of the 41 (of 234) children with likely/pathogenic variants, 26 had variants supporting precision therapy. Multivariate regression modeling highlighted neonatal or infantile-onset seizures and movement abnormalities as predictive of a positive genetic finding. We used this, coupled with an emphasis on precision medicine outcomes, to propose the pragmatic “Think-Genetics” strategy for early recognition of a possible genetic etiology. Conclusion: Our findings emphasize the importance of an early genetic diagnosis in DEE. We designed the Think-Genetics strategy for early recognition, appropriate interim management, and genetic testing for DEE in resource-constrained settings.
| Original language | English (US) |
|---|---|
| Article number | 100333 |
| Journal | Genetics in Medicine |
| Volume | 25 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2023 |
Funding
This work was supported by the National Health Laboratory Service Research Trust (grant numbers 004-94528 [2016-2018] ; 004-94491 [2016]), the South African Medical Research Council [MRC SIR GRANT 2016 – 2019 – UO24508], and National Institutes of Health National Institute of Neurological Disorders and Stroke [NS089858]. Exome sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by National Health Genome Research Institute and National Heart, Lung, and Blood Institute grants UM1 HG006493 and U24 HG008956 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.v We thank all the children and parents for participation and keen interest in the study, which made obtaining and communicating meaningful results so gratifying. We are also grateful to the staff in the Epilepsy Clinic at the Red Cross Children's War Memorial Hospital in Cape Town for the effort put into patient recruitment, obtaining informed consent and browsing patient file archives, adding to their already heavy workload. We would like to acknowledge the contribution of the late Deborah Nickerson to this study, in particular her tireless work in establishing the Center for Mendelian Genomics and finding answers for patients and families searching for the cause of their genetic conditions. This work was supported by the National Health Laboratory Service Research Trust (grant numbers 004-94528 [2016-2018]; 004-94491 [2016]), the South African Medical Research Council [MRC SIR GRANT 2016 – 2019 – UO24508], and National Institutes of Health National Institute of Neurological Disorders and Stroke [NS089858]. Exome sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by National Health Genome Research Institute and National Heart, Lung, and Blood Institute grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.v, Conceptualization: A.I.E. H.C.M. R.R. J.M.W. G.L.C.; Data Curation: A.I.E. G.R. M.W. J.M.W. UW-CMG; Formal Analysis: N.T. M.C.A. J.D.C. J.G. M.J.B.; Funding Acquisition: A.I.E. R.R. J.M.W. G.L.C.; Investigation: A.I.E. M.W. G.R. M.C.A. E.E.A. A.R. J.M.W. G.L.C.; Resources: H.C.M. J.M.W. G.L.C.; Software: R.J.B. J.D.C. J.G.; Supervision: R.R. J.M.W. G.L.C.; Visualization: A.I.E. R.J.B. G.L.C.; Writing-original draft: A.I.E.; Writing-review and editing: A.I.E. N.T. R.J.B. H.C.M. R.R. J.M.W. G.L.C. The study was approved by the Human Research Ethics Committee of the University of Cape Town (HREC REF: 232/2015). Written informed consent (and assent, where appropriate) was obtained from probands and parents before participation in the study.
Keywords
- DEE
- Genetic epilepsy
- Genetic testing
- LMICs
- South Africa
ASJC Scopus subject areas
- Genetics(clinical)