Systematic Review Maps the Genetic Landscape of Epilepsy Across Africa

A systematic review published in Frontiers in Genetics has assembled the most comprehensive picture to date of the genetic architecture of epilepsy in Africa, drawing on 78 studies from 12 of the continent’s 54 countries. The analysis, led by Salia Bamba of the Université des Sciences, des Techniques et des Technologies de Bamako in Mali and Saquib A. Lakhani of Cedars Sinai Guerin Children’s in Los Angeles, identified 1,858 individuals from 384 families, including 519 people with epilepsy of genetic origin and 1,339 unaffected relatives. The studies, published between 2007 and 2025, were overwhelmingly hospital-based case reports and case series, with cohort studies making up just over ten percent of the total.

The geographic concentration of the evidence is striking. Egypt alone accounted for 37.5 percent of the reported families, followed by South Africa at 19.8 percent and Morocco at 15.6 percent, with Tunisia and Mali contributing most of the remainder. Roughly ninety percent of all reported families come from just five countries, and more than two-thirds of African nations have not produced a single publication in epilepsy genetics. The authors searched PubMed, Scopus, Google Scholar, and African Journals Online up to December 2025, restricting inclusion to articles in English and French, a limitation they acknowledge may have excluded work published in other languages.

Methodologically, whole exome sequencing dominated the diagnostic landscape, having been used in 71.8 percent of the included studies. Sanger sequencing followed at 10.3 percent, then gene panels at 6.4 percent, cytogenetic methods at 5.1 percent, and long-read or whole genome sequencing at 3.8 percent. Only the seven cohort studies reported diagnostic yield, with figures ranging from 17.5 to 43.9 percent. Functional validation of identified variants was rare, performed in just 17.9 percent of studies, through cell-based models in 12.8 percent and animal models in 5.1 percent. Most of this functional work took place in laboratories outside Africa through international collaborations, with a single exception: a cell-based study of the PIGT gene conducted in Tunisia in partnership with a laboratory in Japan.

The review catalogued 165 unique diagnostic genes across the cohort, a figure the authors describe as evidence of substantial genetic heterogeneity. Only 12 genes were shared across three or more countries, while 136 genes, or 82.4 percent of those with a defined country distribution, were limited to single countries. SCN1A, a voltage-gated sodium channel gene, was the most broadly distributed, appearing in five countries and accounting for 11.5 percent of the total cohort. In South Africa, SCN1A variants were found in 38.2 percent of families. Other recurrent country-specific genes included ASAH1 in Egypt, identified in 14 unrelated families, ALDH7A1 in Tunisia, found in nine families, and MLC1 in Sudan, present in five of that country’s 13 families.

Founder effects emerged as a defining feature of the continental landscape. Six founder variants accounted for 10.7 percent of the families. Tunisia contributed two: SCN1B c.374G>A in seven families and ALDH7A1 c.1364T>C in nine families. Egypt contributed four: TRAPPC4 c.427A>G in eight families, a CSTB dodecamer repeat expansion in eight families, SNX14 c.-24C>T in three families, and ASAH1 c.155T>C in eight families. Only two identical pathogenic variants were shared across national borders, in SCN1A and KCNT1, both detected in South Africa and Egypt. The authors note that such founder variants could enable population-based carrier screening and earlier genetic counseling in the affected populations.

Consanguinity shaped much of the genetic pattern. Marriage between relatives was documented in 45.6 percent of families, and autosomal recessive inheritance was the most common mode of transmission at 49.5 percent, followed by de novo variants at 32.0 percent. Homozygous variants clustered in countries with the highest consanguinity rates: Egypt reported consanguinity in 65.3 percent of its families, with homozygous variants confined to the genes ASAH1, TRAPPC4, CSTB, and SNX14; Sudan reported consanguinity in 84.6 percent of families, with five carrying homozygous MLC1 variants. By contrast, South Africa displayed heterozygous variants in 93.4 percent of its families, reflecting a different population structure, and Morocco and Mali showed more mixed zygosity profiles.

Variant classification followed the American College of Medical Genetics and Genomics criteria as reported in the source publications. Of 395 identified variants, 50.9 percent were classified as pathogenic, 24.6 percent as likely pathogenic, and 24.6 percent as variants of uncertain significance in established epilepsy genes. Overall, 76.3 percent of families carried pathogenic or likely pathogenic variants, while the remaining 23.7 percent had uncertain-variant findings in genes consistent with their seizure phenotype. Novelty was the rule rather than the exception: 62.0 percent of variants had not been reported previously, and among the novel variants, 67.8 percent were classified as pathogenic or likely pathogenic. Missense changes were the most common variant type at 53.9 percent, followed by frameshift and nonsense variants.

The clinical picture was dominated by severe early-onset disease. Generalized epilepsy was the most common diagnosis at 30.5 percent of families, followed by focal epilepsy at 18.5 percent. Among defined syndromes, unspecified developmental and epileptic encephalopathy led at 31.8 percent, with Dravet syndrome at 7.8 percent and progressive myoclonic epilepsy at 3.6 percent. Age at seizure onset fell in the neonatal and infant period for 52.3 percent of families. Neurodevelopmental delay was reported in 95.6 percent of families, and epilepsy was drug-resistant in 36.2 percent, with treatment data missing for more than half. The authors link the high drug-resistance rate to the predominance of developmental and epileptic encephalopathies, in which pharmacoresistance is a core feature.

Phenotype-genotype correlations showed consistent patterns across borders. SCN1A variants were associated with Dravet syndrome in 79.5 percent of the 44 families carrying them, spanning five countries, with developmental delay in all affected individuals and drug resistance in 61.4 percent. In Tunisia, all nine families with biallelic ALDH7A1 variants had neonatal-onset seizures responsive to pyridoxine supplementation, a notably treatable form of epilepsy representing 19.1 percent of that country’s cohort. CDKL5 variants uniformly caused early infantile epileptic encephalopathy across three countries. Ion channel genes were the largest functional category at 27.3 percent of variants, followed by synaptic function genes at 15.2 percent.

The authors frame their findings as both a foundation and a warning. African populations remain critically underrepresented in public genomic databases, which affects variant classification and clinical interpretation worldwide, and most countries on the continent, particularly in sub-Saharan Africa, lack molecular diagnostic capabilities. The review’s own limitations reinforce the caution: the included cohorts were hospital-based, phenotype reporting was inconsistent across studies, and the concentration of data in North Africa means the results may not reflect the full genetic landscape of the continent. The authors call for multicenter, large-scale studies across different African regions, sustained investment in research infrastructure and training, and deeper involvement of African researchers in international epilepsy initiatives to translate the continent’s extraordinary genetic diversity into clinical benefit.

Subject of Research: A systematic review of epilepsy genetics studies conducted in Africa

Article Title: Epilepsy genetics in Africa: a systematic review

Article References: Bamba, S., Yalcouyé, A., Cissé, L., Kamuli, S., Goita, M. K., Diarra, S., Landouré, G., & Lakhani, S. A. (2026). Epilepsy genetics in Africa: a systematic review. Frontiers in Genetics, 17, Article 1964157. https://doi.org/10.3389/fgene.2026.1964157

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1964157

Keywords: epilepsy, genetics, Africa, systematic review, exome sequencing, founder variants, consanguinity, developmental and epileptic encephalopathy, SCN1A, genomic testing disparities, systematic, review