Variability in gene-sequencing panels could mean missed early-life epilepsy diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report.

NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

Dr. Annapurna Poduri and colleagues from Boston Children's Hospital compared 10 commercially available NGS gene panels from three major vendors (Athena Diagnostics, Ambry Genetics and GeneDx).

These panels varied widely in the number of genes covered: from 10 to 75 genes for early-life epilepsy panels and from 87 to 234 genes for comprehensive epilepsy panels, the team reports in JAMA Pediatrics, online June 4.

All but the largest comprehensive epilepsy panel had incomplete overlap in testing genes, including those with similar indications.

Based on genetic data from an earlier study, early-life epilepsy panels included 7% to 40% of genes reported and, after accounting for some variants reported in multiple patients, these panels would identify between 14% and 61% of reported pathogenic variants.

Similarly, the comprehensive epilepsy panels included 40% to 65% of genes and 61% to 79% of the pathogenic variants represented in the earlier study's patients.

Surprisingly, the yield of one rapid 16-gene panel (45% of pathogenic variants) differed little from the yield of one 67-gene panel (47% of pathogenic variants), suggesting that a bigger panel is not inherently better than a smaller panel.

"In our analysis," the researchers note, "the early-life epilepsy panels would have missed between 41% and 86% of patients with pathogenic variants in confirmed epilepsy genes."

They offer three recommendations: "Research using NGS panels may not be generalizable, and future research should at least report the genes that were tested. Diagnostic laboratories should use published cohorts and current literature to continually update and evaluate their panels. Clinicians must understand that NGS panels are not created equally and may consider discussing test selection with a content expert in epilepsy genetics, such as a consultant in genetics, neurogenetics, or genetic counseling."

https://www.medscape.com/viewarticle/897718

Christopher J. Yuskaitis, Beth Rosen Sheidley, Annapurna Poduri.  Variability Among Next-Generation Sequencing Panels for Early-Life Epilepsies.  JAMA Pediatr 2018.  Online June 4, 2018.  https://bit.ly/2sySdhW

Epilepsy genetics is an emerging field with increasing therapeutic implications resulting from genetic findings. Despite an overall enthusiasm for precision medicine in epilepsy and other disciplines, there remains no consensus on the approach to genetic testing. A recent study by Berg et al3 demonstrated a relatively similar diagnostic yield of epilepsy next-generation sequencing (NGS) gene panels compared with whole-exome sequencing (27% vs 33%). Although the utility of NGS panels are consistently demonstrated  to our knowledge, no study has systematically evaluated the variability in genes tested among clinically available NGS panels. We compared the potential diagnostic yield of commercially available NGS epilepsy panels to detect the genetic findings identified in a recently published cohort of early-life epilepsy.

Methods

We compared 10 commercially available NGS gene panels across 3 major vendors: Athena Diagnostics, Ambry Genetics, and GeneDx. From each source, we evaluated early-life epilepsy panels (eg, infantile spasms, epileptic encephalopathy, and stat [rapid] panels) and comprehensive epilepsy panels as of January 24, 2018. We used the list of pathogenic genetic variants from the study by Berg et al3 to evaluate the theoretical yield for each panel. The Boston Children’s Hospital Institutional Review Board waived approval of this study as it did not involve human participants.

Results

Epilepsy NGS panels displayed a wide range in genes covered: 10 to 75 genes for early-life epilepsy panels and 87 to 234 genes for comprehensive epilepsy panels. Only the largest comprehensive epilepsy panel encompassed all genes on the smaller panels. All other panels had incomplete overlap in tested genes, including those with similar indications (eg, panels for infantile spasms).

We compared the anticipated detection rate for each panel with the genetic findings identified in the study by Berg et al. This analysis reports the yield each panel would have if it were executed today and assuming optimal technical conditions and coverage. Early-life epilepsy panels included 7% to 40% of genes reported in the cohort. Early-life epilepsy panels would identify between 14% and 61% of the reported pathogenic variants in the cohort since some genes (eg, SCN1A [OMIM 182389], STXBP1 [OMIM 602926], and CDKL5 [OMIM 300203]) accounted for multiple patients. The comprehensive epilepsy panels included 40% to 65% of genes and 61% to 79% of the pathogenic variants in the cohort.