Abstract
Although genetic testing is important for bringing precision medicine to children with epilepsy, it is unclear what genetic testing strategy is best in maximizing diagnostic yield. To evaluate the diagnostic yield of an exome-based gene panel for childhood epilepsy and discuss the value of follow-up testing. A case series study was conducted on data from clinical genetic testing at Children's Hospital of Philadelphia was conducted from September 26, 2016, to January 8, 2018. Initial testing targeted 100 curated epilepsy genes for sequence and copy number analysis in 151 children with idiopathic epilepsy referred consecutively by neurologists. Additional genetic testing options were offered afterward. Clinical genetic testing. Molecular diagnostic findings. Of 151 patients (84 boys [55.6%]; median age, 4.2 years [interquartile range, 1.4-8.7 years]), 16 children (10.6%; 95% CI, 6%-16%) received a diagnosis after initial panel analysis. Parental testing for 15 probands with inconclusive results revealed de novo variants in 7 individuals (46.7%), resulting in an overall diagnostic yield of 15.3% (23 of 151; 95% CI, 9%-21%). Twelve probands with nondiagnostic panel findings were reflexed to exome sequencing, and 4 were diagnostic (33.3%; 95% CI, 6%-61%), raising the overall diagnostic yield to 17.9% (27 of 151; 95% CI, 12%-24%). The yield was highest (17 of 44 [38.6%; 95% CI, 24%-53%]) among probands with epilepsy onset in infancy (age, 1-12 months). Panel diagnostic findings involved 16 genes: SCN1A (n = 4), PRRT2 (n = 3), STXBP1 (n = 2), IQSEC2 (n = 2), ATP1A2, ATP1A3, CACNA1A, GABRA1, KCNQ2, KCNT1, SCN2A, SCN8A, DEPDC5, TPP1, PCDH19, and UBE3A (all n = 1). Exome sequencing analysis identified 4 genes: SMC1A, SETBP1, NR2F1, and TRIT1. For the remaining 124 patients, analysis of 13 additional genes implicated in epilepsy since the panel was launched in 2016 revealed promising findings in 6 patients. Exome-based targeted panels appear to enable rapid analysis of a preselected set of genes while retaining flexibility in gene content. Successive genetic workup should include parental testing of select probands with inconclusive results and reflex to whole-exome trio analysis for the remaining nondiagnostic cases. Periodic reanalysis is needed to capture information in newly identified disease genes.
Highlights
Epilepsies are among the most common neurologic disorders, with an estimated prevalence of 6 in 1000 people worldwide.[1]
Parental testing for 15 probands with inconclusive results revealed de novo variants in 7 individuals (46.7%), resulting in an overall diagnostic yield of 15.3% (23 of 151; 95% CI, 9%-21%)
Clinicians are challenged with navigating complex clinical algorithms for choosing the best genetic workup for a specific patient and with test result interpretation,[6,10] clinical laboratories are urged to devise comprehensive testing options, keep testing costs low and turnaround times short, and find solutions for maximizing diagnostic yield while staying abreast of the pace of gene discovery. To address these diverse clinical and economic demands, we have developed an exome sequencing (ES)-based test for the pediatric epilepsy diagnosis focusing on an initial analysis of 100 epilepsy genes
Summary
Epilepsies are among the most common neurologic disorders, with an estimated prevalence of 6 in 1000 people worldwide.[1]. Monogenic forms of seizure disorders tend to manifest earlier in life. Their clinical spectrum is broad, ranging from benign, self-limited epilepsies; epilepsies due to inborn errors of metabolism; epilepsies with other neurodevelopmental issues, such as autism or intellectual disability; and earlyonset, severe epileptic encephalopathies.[4,5,6] Early establishment of a specific diagnosis is necessary for providing an accurate prognosis and recurrence risk as well as optimizing management and treatment options. Pathogenic variants in numerous genes may lead to indistinguishable epilepsies, and variation in the same gene can result in epilepsies with differing presentation, both in severity and comorbidity manifestation.[2,4,6,7,8] genetic testing often serves as a useful tool in finding a definitive cause and concluding the diagnostic process
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
