Abstracts

Rationale:
To assess the reasons for, and potential clinical impact of, delayed genetic diagnosis of SCN1A-related epilepsy.
Method:
We enrolled over 500 children with epilepsy of unknown etiology and non-explanatory brain magnetic resonance imaging in the Boston Children’s Hospital (BCH) Children’s Rare Disease Cohorts Initiative for trio whole exome sequencing (WES). We evaluated four cases with rare, protein-altering variants in the SCN1A gene and reviewed their presentation and genetic testing in the BCH electronic medical record system.
Results:
We identified pathogenic or likely pathogenic SCN1A variants in 4 children with epilepsy (Table 1). Participant 1 is a 4-year-old boy with a clinical diagnosis of Dravet Syndrome. Though his healthcare provider suspected a SCN1A-related etiology, clinical genetic testing was not obtained due to insurance coverage. Participants 2 and 3 are brothers (9 and 11 years of age), each of whom has a clinical diagnosis of Dravet Syndrome. Clinical gene panel testing had been previously pursued for the older brother and identified a variant of uncertain significance (VUS) in SCN1A. The healthcare provider did not pursue parental testing and, due to the VUS classification, the finding was not considered diagnostic. Our analysis of the parents’ WES data revealed that the unaffected mother is mosaic for the variant (14% of reads). Participant 4 is an 8-year-old boy with benign occipital lobe epilepsy with seizure onset at 4 years of age who had no genetic testing prior to enrollment, as his healthcare provider did not consider his phenotype to be suggestive of a genetic etiology. Among the four individuals described, the time elapsed between age at seizure onset and age at molecular diagnosis of the SCN1A variants ranged from 3.4 to 9.8 years.
Conclusion:
Although SCN1A is a well-described epilepsy gene and clinical testing is readily available, we observed that definitive diagnosis of SCN1A-related epilepsy was considerably delayed in our cohort, by as much as a decade. Delays were attributed to a number of factors, including insurance coverage, lack of provider familiarity with the process of variant classification and re-analysis, and consideration of genetic testing for a relatively ‘benign’ epilepsy phenotype. Timely diagnosis of SCN1A-related epilepsy is important for multiple reasons. Recognition that a patient has SCN1A-related epilepsy impacts treatment selection and eligibility for clinical trials and other research studies. Further, molecular diagnosis contributes to accurate genetic counseling regarding recurrence risk for family members and future pregnancies, including in families with known or possible parental mosaicism. Finally, early identification of a genetic etiology spares families a lengthy diagnostic odyssey and enables connection to advocacy and community resources. We advocate for early consideration of genetic testing for patients with unexplained epilepsy, and re-analysis of VUS and additional testing strategies for those who remain ‘unsolved’ after initial evaluation.
Funding:
:BCH Children's Rare Disease Cohorts Initiative