Utility of genetic testing in pediatric epilepsy: Experience from a low to middle-income country
Fizza Akbar1, Raisa Saleh2, Salman Kirmani1
1Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
Insights
Genetic testing for monogenic epilepsies in Pakistan found pathogenic variants in one-third of pediatric patients. This yield is comparable to North America, highlighting the need for South Asian genotype characterization.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Monogenic epilepsies are a key cause of pediatric epilepsy, increasingly diagnosed via genetic testing.
- The effectiveness of genetic testing in low to middle-income countries (LMICs) remains under-investigated.
Purpose of the Study:
- To evaluate the utility and yield of genetic testing for pediatric epilepsy in a LMIC setting.
- To assess the diagnostic yield of next-generation sequencing (NGS) in patients with suspected monogenic epilepsy in Karachi, Pakistan.
Main Methods:
- A retrospective review of 77 pediatric patients with suspected genetic epilepsy who underwent next-generation sequencing (NGS).
- Variant classification using American College of Medical Genetics and Genomics (ACMG) guidelines, including reclassification of variants of uncertain significance (VUSs).
Main Results:
- Initially, 27% of patients had pathogenic (P) or likely pathogenic (LP) results, increasing to 32% after VUS reclassification.
- Post-reclassification, 25% had negative results, and 43% had VUSs; 66% initially had at least one VUS.
- The diagnostic yield was comparable to North American cohorts, with a higher proportion of P/LP variants in *SCN1A*, including two novel variants.
Conclusions:
- Genetic testing is effective for diagnosing pediatric epilepsy in LMICs, with a diagnostic yield comparable to high-income countries.
- A significant proportion of VUSs initially complicates interpretation, underscoring the need for better characterization of the South Asian genotype.
- Further research into population-specific genetic variations is crucial for improving diagnostic accuracy in diverse populations.
Abstract:
Monogenic epilepsies are a significant etiology of pediatric epilepsy. These are now more easily identified due to advances in genetic testing. However, the utility of genetic testing in low to middle-income countries (LMICs) has not been fully explored. A retrospective review was carried out in Karachi, Pakistan. Patients with symptoms suggestive of genetic epilepsy underwent next-generation sequencing (NGS). Seventy-seven patients were tested, of which 27 % (n = 21) initially had pathogenic (P) or likely pathogenic (LP) results. This increased to 32 % (n = 25) after clinical reclassification of some variants of uncertain significance (VUSs) based on American College of Medical Genetics and Genomics (ACMG) guidelines. Initially, 6 % of patients (n = 5) had no P/LP or VUS, and 66 % (n = 51) had at least one VUS. After variant resolution and reclassification, results were negative for 25% (n = 19) and 43% (n = 33) had VUSs. Genetic testing was positive in one-third of our population. The proportion of P/LP variants found in SCN1A is higher than that found in other populations, and we report two novel variants in SCN1A. The yield of genetic testing in our population is comparable to that found in North America. Initially, a higher proportion of our population had inconclusive results, indicating the need for better characterization of the South Asian genotype.
