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Exome-based screenings may allow for maximum diagnostic yield in an increasingly crowded field of genetic tests.
Ahmad Abou Tayoun, PhD
Exome-based genetic testing panels are a promising diagnostic modality for patients with childhood-onset idiopathic epilepsy, allowing for both rapid analysis of results as well as flexibility in gene content.
The results, published in JAMA Network Open, suggest that exome-based screenings may allow for maximum diagnostic yield in an increasingly crowded field of genetic tests.
“Over the past decade, the number of genes implicated in epilepsy and the repertoire of genetic tests offered have grown significantly. Each of those tests comes with its own advantages and limitations in terms of detectable genetic variant type, diagnostic yield, costs, and turnaround time,” wrote the investigators, led by Ahmad Abou Tayoun, PhD, of Children’s Hospital of Philadelphia and Al Jalila Children’s Specialty Hospital in Dubai, United Arab Emirates. “Although clinicians are challenged with navigating complex clinical algorithms for choosing the best genetic workup for a specific patient and with test result interpretation, 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.”
Tayoun and colleagues conducted a case series analysis of 151 patients, age 0 to 22, who presented with epilepsy of unknown origin and who were referred for genetic testing. Seizure types reported included focal (40.4%), generalized (32.5%), and mixed-type seizures (17.2%).
The initial exome panel, which targeted 100 curated epilepsy genes for sequence and copy number analysis, resulted in a diagnosis in 16 patients (10.6%). Additional testing, including parental screening for 15 probands and reflex exome sequencing of 12 probands resulted in an overall diagnostic yield of 17.9%. The yield was highest among probands with onset in infancy (38.6%).
Findings from the panel implicated 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), while additional exome sequencing identified 4 (SMC1A, SETBP1, NR2F1, and TRIT1). Additional analysis of 13 genes implicated in epilepsy since the launch of the panel resulted in diagnostic findings for 6 patients.
“In addition to being a useful testing option, this exome-based approach may enable flexible update of panel gene content with minimal test validation to keep up with the continuous discovery of new epilepsy genes, and also allows periodic reanalysis on patients with nondiagnostic results,” the investigators wrote.
The results emphasize the importance of follow-up and parental screening, with the authors recommending that “parental samples be obtained simultaneously with the proband’s because parental samples are necessary for interpretation of identified variants.” They also suggest that initial exome panel testing on a family trio could be considered as an option to help reduce the need for follow-up, increase the confidence in the findings, and decrease the time to diagnosis, although at an increased cost.
However, they concluded that “this moderate increase in testing cost might be worthwhile given the health care benefits of the shortened time to diagnosis, which is not only associated with reduced overall cost of the patient's diagnostic workup, but would also be of significance for delivering timely, personalized treatments.”
Balciunience J, DeChene ET, Akgumus G, et al. Use of a dynamic genetic testing approach for childhood-onset epilepsy. JAMA Network Open. Published online April 12, 2019. doi: :10.1001/jamanetworkopen.2019.2129