Somatic Mutations in Human Temporal Lobe Epilepsy
Abstract number :
2.324
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204344
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Russell Buono, PhD – Cooper Medical School of Rowan University; Michael Sperling, MD – Professor, Director, Comprehensive Epilesy Center, Thomas Jefferson University Hospital; Yichuan Liu, Ph.D. – Informatics, Center for Applied Genomics, The Children's Hospital of Philadelphia; Courtney Vaccaro, Ph.D. – Informatics, Center for Applied Genomics, The Children's Hospital of Philadelphia; Renata Pellegrino Da Silva, Ph.D. – Assistant Professor, Center for Applied Genomics, The Children's Hospital of Philadelphia; Thomas Ferraro, Ph.D. – Professor, Biomedical Sciences, Cooper Medical School of Rowan University; Hakon Hakonarson, MD Ph.D. – Professor, Director, Center for Applied Genomics, The Children's Hospital of Philadelphia
Rationale: Genetic influences on human epilepsy are complex. Most work done to identify gene mutations in patients with various forms of common and rare epilepsy analyzed gene structure in DNA derived from peripheral blood. We hypothesize that somatic mutations exist in the brain cells of most individuals and that specific allelic variations influence both susceptibility and resistance to epilepsy and other brain diseases. Thus, somatic cell mutations may contribute to the cause of epilepsy in humans.
Methods: Five temporal lobe epilepsy patients were studied using whole exome sequencing (WES) at an average of >100X depth of coverage. DNA was isolated from peripheral blood and from a single region of the resected temporal neocortex (Brodmann area 38) and WES performed to compare results between blood sequences and brain sequences in each patient (n=5). Bioinformatics analysis were used to identify mutations found in brain WES that were not found in blood WES for each patient studied. The mutations were separated into “rank A” which are nonsense somatic mutations (stop-gain, frameshift deletion/insertion etc.) and “rank B” which are non-synonymous mutations. Mutations were called based on a minimum minor allele frequency (MAF) of >= 1% based on read number and depth of coverage.
Results: We identified thousands of somatic mutations in each of the 5 patients. In total, there were 4010 unique genes that contain at least one rank A somatic mutation with 191 of these genes represented at an MAF >5%. We identified 8388 unique genes with rank B mutations. The five patients had 20 genes with rank A somatic mutations in common including: CCDC30, HMCN1, OR2T2, TTN, XIRP1, FRAS1, MAML3, TACC2, MKI67, ACIN1, RBM25, SLTM, BRD7, HNF1B, FHOD3, DPP9-AS1, MUC16, NRIP1, LOC150051, and CLTCL. The five patients had 54 genes with rank B somatic mutations in common.
Conclusions: Somatic mutations occur in the brain cells of patients with temporal lobe epilepsy and these may contribute to seizure development. Twenty genes with mutations were identified in all five patients, two of which were previously associated with epilepsy (BRD7 and CLTCL). It is likely that somatic mutations occur in many humans and specific allelic variations influence both susceptibility and resistance to epilepsy and other brain diseases. We are currently expanding the number of blood-brain pairs and the number of brain regions, including additional areas of temporal neocortex as well as hippocampus and amygdala. Convergence of somatic gene mutations and single cell or bulk tissue gene expression profiles may help identify new brain cell-localized, genetic causes of epilepsy.
Funding: Funded by a grant to RJ Buono from the Camden Health Research Initiative of Rowan University
Genetics