Precision medicine for developmental and epileptic encephalopathies in Africa-strategies for a resource-limited setting

Alina I Esterhuizen; Nicki Tiffin; Gillian Riordan; Marie Wessels; Richard J Burman; Miriam C Aziz; Jeffrey D Calhoun; Jonathan Gunti; Ezra E Amiri; Aishwarya Ramamurthy; Michael J Bamshad; University of Washington Centre for Mendelian Genomics (UW-CMG); Heather C Mefford; Raj Ramesar; Jo M Wilmshurst; Gemma L Carvill

doi:10.1016/j.gim.2022.11.002

Precision medicine for developmental and epileptic encephalopathies in Africa-strategies for a resource-limited setting

Genet Med. 2023 Feb;25(2):100333. doi: 10.1016/j.gim.2022.11.002. Epub 2022 Dec 8.

Authors

Alina I Esterhuizen¹, Nicki Tiffin², Gillian Riordan³, Marie Wessels³, Richard J Burman⁴, Miriam C Aziz⁵, Jeffrey D Calhoun⁵, Jonathan Gunti⁵, Ezra E Amiri⁵, Aishwarya Ramamurthy⁵, Michael J Bamshad⁶; University of Washington Centre for Mendelian Genomics (UW-CMG); Heather C Mefford⁷, Raj Ramesar¹, Jo M Wilmshurst⁸, Gemma L Carvill⁹

Collaborators

University of Washington Centre for Mendelian Genomics (UW-CMG):
Michael J Bamshad, Suzanne M Leal, Deborah A Nickerson, Peter Anderson, Tamara J Bacus, Elizabeth E Blue, Katherine Brower, Kati J Buckingham, Jessica X Chong, Diana Cornejo Sánchez, Colleen P Davis, Chayna J Davis, Christian D Frazar, Katherine Gomeztagle-Burgess, William W Gordon, Martha Horike-Pyne, Jameson R Hurless, Gail P Jarvik, Eric Johanson, J Thomas Kolar, Colby T Marvin, Sean McGee, Daniel J McGoldrick, Betselote Mekonnen, Patrick M Nielsen, Karynne Patterson, Aparna Radhakrishnan, Matthew A Richardson, Gwendolin T Roote, Erica L Ryke, Isabelle Schrauwen, Kathryn M Shively, Joshua D Smith, Monica Tackett, Gao Wang, Jeffrey M Weiss, Marsha M Wheeler, Qian Yi, Xiaohong Zhang

Affiliations

¹ The 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.
² South African National Bioinformatics Institute, University of the Western Cape, Bellville, Western Cape, South Africa.
³ Department of Paediatric Neurology, Red Cross War Memorial Children's Hospital, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁴ Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
⁵ Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL.
⁶ Department of Pediatrics, University of Washington, Seattle, WA; Department of Genome Sciences, University of Washington, Seattle, WA; Brotman Baty Institute, Seattle, WA.
⁷ Centre for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN.
⁸ Department of Paediatric Neurology, Red Cross War Memorial Children's Hospital, Neuroscience Institute, University of Cape Town, Cape Town, South Africa. Electronic address: jo.wilmshurst@uct.ac.za.
⁹ Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address: gemma.carvill@northwestern.edu.

PMID: 36480001
DOI: 10.1016/j.gim.2022.11.002

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: DEE; Genetic epilepsy; Genetic testing; LMICs; South Africa.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Africa
Child
Epilepsy* / diagnosis
Epilepsy* / epidemiology
Epilepsy* / genetics
Genetic Testing
Humans
Infant, Newborn
Precision Medicine*
Resource-Limited Settings

Abstract

Publication types

MeSH terms

Grants and funding