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Precision medicine for developmental and epileptic encephalopathies in Africa-strategies for a resource-limited
Alina I Esterhuizen1, Nicki Tiffin2, Gillian Riordan3
1The South African MRC/UCT Genomic and Precision Medicine Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa.
Insights
Genetic testing in South African children with developmental and epileptic encephalopathies (DEEs) identified actionable variants in over 15% of cases. A new "Think-Genetics" strategy aids early recognition and genetic testing for DEEs in resource-limited areas.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Sub-Saharan Africa faces the highest global epilepsy burden, with a significant, yet underdiagnosed, genetic component.
- Children with developmental and epileptic encephalopathies (DEEs) are disproportionately affected by diagnostic gaps, particularly in identifying genetic causes.
- Limited awareness and testing options exacerbate the challenge of diagnosing genetic etiologies in African children.
Purpose of the Study:
- To investigate the utility of genetic testing in South African children with suspected DEEs.
- To identify clinical features predictive of positive genetic findings in this population.
- To propose a pragmatic strategy for early genetic diagnosis of DEEs in resource-constrained settings.
Main Methods:
- Genetic analysis of 234 children with suspected DEEs using gene panels, exome sequencing, and chromosomal microarray.
- Statistical comparison of electroclinical features between children with and without identified candidate variants.
- Multivariate regression modeling to pinpoint predictive characteristics for positive genetic results.
Main Results:
- Likely/pathogenic variants were identified in 41 out of 234 children (17.5%).
- Twenty-six children had variants associated with precision therapy options.
- Neonatal/infantile-onset seizures and movement abnormalities were significant predictors of positive genetic findings.
Conclusions:
- Early genetic diagnosis is crucial for children with DEEs, enabling precision medicine approaches.
- The "Think-Genetics" strategy promotes early recognition, appropriate management, and genetic testing for DEEs.
- Implementing this strategy can improve outcomes for DEE patients in resource-limited settings.
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.
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