Authors :
Presenting Author: Mark Fitzgerald, MD PhD – Children's Hospital of Philadelphia
Julie Xian, BS – Children's Hospital of Philadelphia; Michael Kaufman, MS – Children's Hospital of Philadelphia; Sarah Ruggiero, MS CGC – Children's Hospital of Philadelphia; Mark Ramos, BS – Children's Hospital of Philadelphia; Alexander Gonzalez, MS MBA – Children's Hospital of Philadelphia; Amanda Back, MS CGC – Children's Hospital of Philadelphia; Lea Bailey-Medley, MBA – Children's Hospital of Philadelphia; Stacey Cohen, MS CGC – Children's Hospital of Philadelphia; Vishnu Cuddapah, MD PhD – Children's Hospital of Philadelphia; Holly Dubbs, MS CGC – Children's Hospital of Philadelphia; Colin Ellis, MD – Children's Hospital of Philadelphia; Natalie Ginn, MGC CGC – Children's Hospital of Philadelphia; Naomi Lewin, MD PhD – Children's Hospital of Philadelphia; Laina Lusk, MMSc CGC – Children's Hospital of Philadelphia; Eric Marsh, MD PhD – Children's Hospital of Philadelphia; Shavonne Massey, MD MSCE – Children's Hospital of Philadelphia; Xilma Ortiz-Gonzalez, MD PhD – Children's Hospital of Philadelphia; Pamela McDonnell, MD – Children's Hospital of Philadelphia; Katherine Sullivan, MS CGC – Children's Hospital of Philadelphia; Katherine Taub, MD – Children's Hospital of Philadelphia; Sarah Tefft, MSN CRNP – Children's Hospital of Philadelphia; Katherine Helbig, MS CGC – Children's Hospital of Philadelphia; Ethan Goldberg, MD PhD – Children's Hospital of Philadelphia; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
Epilepsies with presumed genetic etiologies account for up to two thirds of all epilepsies. With the advent of massive parallel sequencing in the last decade, more than 1,000 unique genetic etiologies have been identified. The identification of a genetic etiology can have critical implications for clinical management and a comprehensive genetic work-up is increasingly considered standard of care in unexplained epilepsy.Methods:
We retrospectively assessed genetics evaluations and clinical care of 3,760 consecutive individuals with epilepsy and neurodevelopmental disorders seen at a large pediatric healthcare network over three years. The utilization and diagnostic yield of clinical genetic testing was analyzed across sequencing modalities such as whole-exome and targeted sequencing. The impact of a molecular diagnosis on subsequent clinical management was reviewed, including referrals to specialty care and epilepsy surgical evaluations, and modifications to anti-seizure medications and treatment strategies. Seizure outcomes across epilepsy syndromes and genetic etiologies were assessed using a Common Data Element-based framework.Results:
Nine hundred thirty individuals underwent whole exome sequencing (22% yield), 1,346 underwent a gene panel (13% yield), 360 underwent a chromosomal microarray (7% yield), 34 underwent single gene testing (21% yield), and 189 underwent another testing modality. The median age of genetic diagnosis was 3.1 years. The most common genetic etiologies diagnosed in our cohort were SCN1A (n=18), KCNQ2 (n=17), PRRT2 (n=12), DEPDC5 (n=10), and NPRL3 (n=10). Seizure frequencies were systematically documented for 2,311 individuals over a cumulative 1,625 patient-years. Assessment of systematic changes in patient management following a genetic diagnosis demonstrated measurable effects on patient outcomes including seizure frequencies, shifts in medication prescription practices, and referrals to epilepsy surgery.
Conclusions: Our study demonstrates a high diagnostic yield for genetic testing in individuals with epilepsy and neurodevelopmental disorders. We establish a framework for systematic characterization of real-world clinical care and show that ongoing evaluation of genetic etiologies has critical implications for individualized clinical care and precision medicine avenues.
Funding:
This work was supported by The Hartwell Foundation, the National Institute for Neurological Disorders and Stroke, and the Children’s Hospital of Philadelphia.