Exploring De Novo Pathogenic Variants and Gene Associations in Epilepsy Patients with Comorbid Autism Spectrum Disorder
Abstract number :
3.365
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
1217
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Lea Erjavc, MSc – Icahn School of Medicine at Mount Sinai
Xiao Lin, PhD – Icahn School of Medicine at Mount Sinai; Byron Ramirez, BSc – Icahn School od Medicine at Mount Sinai; Maite LaVega-Talbott, MD – Icahn School of Medicine; Hillary Raynes, MD – Icahn School of Medicine at Mount Sinai; Lara Marcuse, MD – Icahn school of Medicine at Mount Sinai; Madeline Fields, MD – Icahn school of Medicine at Mount Sinai; Patricia McGoldrick, MP – Boston Children’s Health Physicians; Orrin Devinsky, MD – Neurology, New York University/Langone Health; Steven Wolf, MD – Neurology, Boston Children’s Health Physicians, Maria Fareri Children's Hospital at Westchester Medical Center; Dalila Pinto, PhD – icahn School of Medicine at Mount Sinai
Rationale: Epilepsy is a complex neurological disorder often associated with comorbid conditions such as autism spectrum disorder (ASD). Understanding the genetic basis of epilepsy and its relationship with ASD is crucial for improving diagnosis and treatment strategies. This study aims to identify de novo pathogenic variants in epilepsy, assess their prevalence in ASD, and explore novel gene associations implicated in epilepsy.
Methods: We enrolled a new family cohort ascertained from the New York state area consisting of > 673 individuals with epilepsy, of which 471 (70%) were also diagnosed with ASD. Genomic DNA was extracted from peripheral blood (90%) and saliva samples (10%) and screened using both SNP microarrays and exome or whole-genome sequencing (WES/WGS). For microarray, copy number variant (CNV) analysis was conducted to identify primarily de novo pathogenic variants in individuals with epilepsy. Moreover, WES data was filtered to confirm SNV frequency together with other filtering steps to find protein-truncating, missense and splice site alterations.
Results: Through our analysis using microarray based CNV analysis, we discovered a notable presence of more than 200 pathogenic variants in the study cohort, of which several were unique to individuals with epilepsy with comorbid ASD. Subsequently, the utilization of whole-exome sequencing enabled us to validate and identify several of these variants, further strengthening the evidence of their pathogenic nature. Moreover, the WES analysis revealed the occurrence of single nucleotide variants (SNVs) in genes associations with epilepsy, occurring in more than one individual. Ultimately, the integration of pathogenicity from CNV analysis with SNV data pinpointed to genes of significance. This comprehensive approach significantly enhanced our understanding of the genetic landscape that underlies this condition.
Conclusions: Our study demonstrates the utility of combining microarray CNV analysis and WES to identify de novo pathogenic variants in epilepsy patients, with particular focus on those with ASD. Additionally, our findings highlight the potential of WES in discovering novel gene associations related to epilepsy. This research contributes to the growing body of knowledge surrounding the genetic basis of epilepsy and may inform future diagnostic and therapeutic approaches of patients with epilepsy and ASD.
Funding: NIH
Genetics