Authors :
Presenting Author: Katelyn Stone, BS – Boston Children's Hospital
Abbe Lai, MS, CGC – McGill University
Gillian Prinzing, MS, CGC – Boston Children's Hospital
Lacey Smith, MS, CGC – Boston Children's Hospital
Beth Sheidley, MS, CGC – Boston Children's Hospital
Annapurna Poduri, MD, MPH – Boston Children's Hospital
Alissa D'Gama, MD, PhD – Boston Children's Hospital
Rationale:
Deep sequencing in the research setting has established that somatic mosaicism is an important genetic mechanism underlying lesional focal epilepsies. Because the pathogenic mosaic variants are largely brain-limited, these discoveries have relied on brain tissue samples from patients with drug resistant epilepsy who have epilepsy surgery. Clinical genetic testing for patients with epilepsy primarily detects germline variants using accessible samples like blood or buccal swabs. Thus, a gap exists between mosaic variant detection in the research setting and translating these methods to the clinical setting. We aimed to determine the diagnostic yield of implementing clinical deep sequencing for patients with malformations of cortical development (MCDs) and epilepsy at our institution.
Methods:
We abstracted demographic, clinical, and genetic testing data for patients with MCDs and epilepsy at Boston Children’s Hospital who had clinical deep sequencing performed from 2017—present. We initially used a clinical deep sequencing panel for Somatic Overgrowth developed by the Clinical Genomics Laboratory at Washington University in St. Louis. We assisted this laboratory with gene selection and validation for a new clinical deep sequencing panel for Cortical Malformations and Epilepsy, and subsequently transitioned to using that panel. We analyzed summary statistics and compared the diagnostic yield between affected and non-affected tissue samples using a two-tailed Fisher’s exact test.
Results:
We analyzed 20 patients with MCDs who received clinical deep sequencing; 13 female and 7 male. Of the 18 patients with epilepsy, most had neonatal or infantile seizure onset (12/18); 2 patients with MCDs had no reported seizures. For the 15 patients where clinical deep sequencing was performed using samples from affected tissue, pathogenic mosaic variants were detected in 9/15, a diagnostic yield of 60%. The mosaic variants included single nucleotide variants in AKT3 (2), BRAF, MTOR (2), PIK3CA (2), and TSC2 as well as a 1q gain. The diagnosed cases included five patients with epilepsy and MCDs who had brain tissue tested, one patient with epilepsy and a MCD on imaging subsequently confirmed as a low-grade glioneuronal tumor on pathology who had brain tissue tested, and three patients with epilepsy and MCDs in the setting of systemic megalencephaly-capillary malformation syndrome who had non-brain tissue tested. For the 5 patients with MCDs where clinical deep sequencing was performed using samples from unaffected tissue, the diagnostic yield was 0%. The diagnostic yield was significantly higher when affected vs unaffected tissue was tested (p=0.0379).
Conclusions:
Clinical deep sequencing, when performed using an affected tissue sample, has high diagnostic utility for patients with MCDs and epilepsy. Our findings support implementation of clinical deep sequencing for this population, especially as the genetic diagnoses have implications for emerging precision therapies and clinical trials.
Funding: None