Genetic Diagnosis Impacts Medical Management for Pediatric Epilepsies

Abstract

Background: Evidence of the impact of genetic diagnosis on medical management in individuals with previously unexplained epilepsy is lacking in the literature. Our goal was to determine the impact of genetic diagnosis on medical management in a cohort of individuals with early-onset epilepsy.

Methods: We performed detailed phenotyping of individuals with epilepsy who underwent clinical genetic testing with an epilepsy panel and/or exome sequencing at Boston Children's Hospital between 2012 and 2019. We assessed the impact of genetic diagnosis on medical management.

Results: We identified a genetic etiology in 152 of 602 (25%) individuals with infantile- or childhood-onset epilepsy who underwent next-generation sequencing. Diagnosis impacted medical management in at least one category for 72% of patients (110 of 152) and in more than one category in 34%. Treatment was impacted in 45% of individuals, including 36% with impact on antiseizure medication choice, 7% on use of disease-specific vitamin or metabolic treatments, 3% on pathway-driven off-label use of medications, and 10% on discussion of gene-specific clinical trials. Care coordination was impacted in 48% of individuals. Counseling on a change in prognosis was reported in 28% of individuals, and 1% of individuals had a correction of diagnosis. Impact was documented in 13 of 13 individuals with neurotypical development and in 55% of those with epilepsy onset after age two years.

Conclusion: We demonstrated meaningful impact of genetic diagnosis on medical care and prognosis in over 70% of individuals, including those with neurotypical development and age of epilepsy onset after age two years.

Keywords: Development; Epilepsy; Next-generation sequencing; Precision treatment; Whole exome sequencing.

FIGURE 1.

Study flowchart. Inclusion/exclusion criteria, genetic testing algorithm, and results of our cohort. Figure created with BioRender.com. *For two individuals, exome reanalysis was done after clinical exomes with diagnostic findings in AGO1 and CHAT to look for further contribution to epilepsy phenotypes that were more severe than expected. No additional findings were identified. ^$In 13 of 14, panel was done to expand genetic evaluation when exome was nondiagnostic or did not fully explain the phenotype, including full coverage of updated epilepsy genes and copy number variant analysis. In one additional patient, rapid exome was sent while panel was pending due to severity of the medical condition.

FIGURE 2.

Implicated genes for epilepsy diagnosis in a clinical cohort of 602 individuals with infantile- or childhood-onset epilepsy from Boston Children’s Hospital. Genes with variants identified on panel or exome thought to clinically explain epilepsy for 152 individuals, 130 with epilepsy onset less than or equal to two years of age. The most common genes for which causative variants were identified included SCN1A (n = 19), KCNQ2 (n = 12), PRRT2 (n = 8), SCN2A (n = 7), CDKL5 (n = 6), CHD2 (n = 5), TSC2 (n = 4) STXBP1 (n = 4), SCN8A (n = 4) CHD2 and SCN8A, which were later added to panels, were identi fied on both panels and exomes in our series.

FIGURE 3.

Implicated genes for epilepsy diagnosis in a clinical cohort of 183 individuals with infantile- or childhood-onset epilepsy from Boston Children’s Hospital and initial negative epilepsy gene panel testing. Genes with causative variants identified on clinical or research exome, following a nondiagnostic panel, in 54 individuals with epilepsy, 48 with age of epilepsy onset less than or equal to two years. The genes for which causative variants were identified in more than one individual included DYNC1H1 (n = 3), ALG11(n = 2), CHD2 (n = 2), FRRS1L (n = 2), NEXMIF (n = 2), PACS2 (n = 2), SCN8A (n = 2), and WDR45 (n = 2).