Published on in CHOP News
Children’s Hospital of Philadelphia (CHOP) researchers have reported results from their clinical genetic test for childhood epilepsy, showing the importance of including parental testing to clarify molecular findings. The testing strategy is based on exome sequencing, with initial analysis of selected genes, and the opportunity to expand to a full genome analysis.
“One common problem in clinical genetic testing is that many results are initially inconclusive,” said Jorune Balciuniene, PhD, the first author of a study published April 12, 2019, in JAMA Network Open. “Currently, when we test pediatric epilepsy patients for epilepsy-related gene variants, we typically obtain a definitive diagnosis in only about 1 in 10 patients. Childhood epilepsy is complex, and having a molecular diagnosis is important for patient management and treatment.”
Balciuniene and colleagues from the Division of Genomic Diagnostics (DGD), along with clinicians Ingo Helbig, MD, Ethan Goldberg, MD, PhD, and Eric Marsh, MD, PhD, from the CHOP Epilepsy Neurogenetics Initiative (ENGIN), reported on findings from a cohort of 151 CHOP patients with idiopathic (of unknown cause) childhood epilepsy. The study, conducted at CHOP, was led by Ahmad Abou Tayoun, PhD, now at Al Jalila Children’s Specialty Hospital in Dubai, United Arab Emirates.
The diagnostic team used an exome-sequencing based epilepsy testing panel, recently launched by the DGD, that includes 100 well-curated epilepsy genes. After the initial analysis, the test yielded a diagnosis in 16 of 151 children (11%). “The usual approach for such tests is a ‘one and done’ strategy on only the probands — the patients referred for the test,” said Balciuniene. “Here, we also evaluated the contribution of additional follow-up testing, when the panel test on a proband had non-diagnostic (inconclusive or negative) results. We performed parental testing, as well as full exome analysis of family trios — the child and both parents. The follow-up testing increased the overall diagnostic yield to 18%, even though only 20%of probands underwent follow-up testing.”
Balciuniene added that follow-up parental testing alone for only 15 probands with inconclusive panel findings revealed diagnosis in seven of them, which increased the diagnostic rate in the cohort by almost 50%, from 11% to 16%. For some probands, parental testing revealed that the suspect variants were clinically insignificant, which helped to further reduce the diagnostic uncertainty. Overall, parental testing resulted in a 70% reduction of inconclusive findings. Knowing whether a particular gene variant is inherited or appears spontaneously in a patient helps determine whether the variant is disease-causing or not. “This highlights how important it is to have parental samples available, to allow us to better interpret genetic results,” she added.
Moreover, having exome-based testing data allows for regular reanalysis in the future, as scientists continue to discover new epilepsy-related genes. “As we increase our understanding of epilepsy at the genetic level, it is our hope that we can better use diagnostics to guide more precise treatment,” said Nancy B. Spinner, PhD, Chief of the DGD and a co-author of the paper. “Clinicians will be able to provide more targeted treatments and intervene at earlier ages.”
Jorune Balciuniene et al, Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy,” JAMA Network Open, published online April 12, 2019.
Contact: The Children’s Hospital of Philadelphia,