Clinical Utility of Genome Sequencing in Exome Negative Individuals with Early Onset Epilepsy
Abstract number :
1.347
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1825724
Source :
www.aesnet.org
Presentation date :
12/9/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Malavika Hebbar, MBBS PhD - BC Children's Hospital; Phillip Richmond, PhD – Scientist, Medical Genetics, BC Children's Hospital; Inderpal Gill, BSc – Research Coordinator, Pediatrics, BC Children's Hospital; Conrado DeGuzman, MD – Research Coordinator, Pediatrics, BC Children's Hospital; Areesha Salman, MSc CGC – BC Children's Hospital; Joshua Dalmann, BS – Pediatrics – BC Children's Hospital; Daniel Evans, MD PhD – Medical Genetics – University of British Columbia; Cyrus Boelman, MD – Pediatrics – BC Children's Hospital; Linda huh, MD FRCPC – BC Children's Hospital; Stuart Turvey, MBBS DPHIL FRCPC – BC Children's Hospital; Matthew Farrer, PhD – Medical Genetics – University of British Columbia; Anna Lehman, MD FRCPC MA CCMG – Medical Genetics – BC Children's Hospital; Mary Connolly, FRCP MBBCH – Pediatrics – BC Children's Hospital; Michelle Demos, MD FRCPC – Pediatrics – BC Children's Hospital
Rationale: The diagnostic yield of exome sequencing in epileptic encephalopathies and mixed epilepsy cohorts ranges between 10 and 60%. Previously, we noted 33% diagnostic yield of exome sequencing in early onset epilepsy. Advances in bioinformatics and genomic technologies have advanced the clinical utility of genetic testing for epilepsy, allowing us to explore beyond protein coding region of the genome. In this work, we assess the clinical utility of genome sequencing in 16 families with early onset epilepsy and epileptic encephalopathy.
Methods: Subjects with undefined cause of severe early onset epilepsy ( < 18 months) after clinical evaluation, EEG, brain MRI, chromosome microarray and exome sequencing (Ion ProtonTM) were recruited in the study. Genome sequencing (Illumina, San Diego, CA, United States) was performed in 16 families. Most of the families underwent trio testing with exceptions of a quad and a singleton. We used an in-house, open source, semi-automated bioinformatics pipeline for analysis. Data was evaluated in phases for single nucleotide variants, indels, mitochondrial variants, repeat expansions, mobile elements and structural variants. It was followed by confirmatory testing.
Results: We have completed screening for SNVs, indels, and mitochondrial variants. The analysis is in progress. A definite molecular diagnosis is achieved in 20% of the cohort (STXBP1, CDKL5, TBR1). Additional candidate genes in epilepsy are identified in 27% including an amino acid transporter as a potential novel gene in early onset epilepsy. Mutation spectrum comprise of two frameshift deletions, two missense, a synonymous variant with potential splicing effects, a frameshift insertion, an in-frame deletion and an intronic deletion.
Conclusions: The diagnostic exonic variants (all indels) that were missed in exome sequencing can be attributed to the known limitations of the Ion Proton platform for detecting indels. We describe the diagnostic yield, potential impact on treatment, and novel genetic etiologies obtained by genome sequencing and explain the importance of performing genome sequencing in exome negative individuals with epilepsy.
Funding: Please list any funding that was received in support of this abstract.: Canada Excellence Research Chair and Leading Edge Endowment funds, Rare Disease Foundation, Grocholski Foundation, Alva Foundation, and BC Children's Hospital Foundation.
Genetics