Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

Abstract

Objective We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well‐phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. Methods We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection‐related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Results Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy‐related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Significance Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well‐phenotyped patients with epilepsy leads to a broader understanding of gene‐specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease‐associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

“…The clinical utility of WES in DEE adult patients is rarely investigated, with very little research conducted mainly on mixed‐age populations, reporting a diagnostic yield in adults ranging between 27% and 33.3% 7‐9 . Compared to the one reached in unrelated pediatrics patients (range 21.3%‐42% 3,4,6‐9 ), it is likely that the result in adults may be biased by the difficulty to retrieve blood samples of older family members, making the VoUS interpretation challenging, even when consistent with the phenotype.…”

“…As DEE are predominantly pediatric disorders, most of the initial implementations of NGS in a clinical setting have been addressed to newborns and children, 3‐6 while less attention has been paid to adult DEE patients who never underwent next generation genetic tests 7‐9 …”

“…newborns and children, [3][4][5][6] while less attention has been paid to adult DEE patients who never underwent next generation genetic tests. [7][8][9] This population of undiagnosed adult patients represents the socalled "lost generation," 10 who had to experience the frustration of "diagnostic odysseys" characterized by inconclusive gene-by-gene tests along decades, prior to the advent of NGS techniques.…”

Clinical Utility of Exome Sequencing and Reinterpreting Genetic Test Results in Children and Adults With Epilepsy

“…Indeed, the American College of Medical Genetics and Genomics (ACMG) has proposed that previously reported genetic variants be periodically reviewed (Richards et al, 2015;Deignan et al, 2019). Thus, owing to the rapid advances in publicly available databases and the ongoing updating of the clinical phenotypes of the patients, it is particularly important in epilepsy to periodically reinterpret genetic test reports (Epilepsy Genetics Initiative, 2019;Rochtus et al, 2020). Here, we aimed to evaluate the clinical utility and diagnostic potential of reinterpreting NGS results in a cohort of 200 pediatric and adult epileptic patients.…”

Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

“…In humans, it was recently reported that patients with homozygous loss-of-function mutations in the ITPA gene showed severe encephalopathy with epileptic seizure and microcephaly or dilated cardiomyopathy. Furthermore, all patients showed developmental retardation, and most died before 4 years of age (3,(20)(21)(22)(23).…”