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.
Keywords
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Article info
Publication history
Published online: December 08, 2022
Accepted:
November 1,
2022
Received in revised form:
October 31,
2022
Received:
July 20,
2022
Publication stage
In Press Corrected ProofFootnotes
Raj Ramesar, Jo M. Wilmshurst, and Gemma L. Carvill contributed equally.
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
