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Abstract Details

Research-to-Clinical Results of Trio Exome Sequencing in a Large, Single-Center Epilepsy Cohort
Child Neurology and Developmental Neurology
Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)
081

To demonstrate the high yield and utility of trio whole exome sequencing (WES) in children with unexplained epilepsy through a prospectively enrolling, single-center research study that combines phenotypic and genomic expertise to deliver clinically returned genetic results.
Despite growing recognition of the important role of genetics in pediatric epilepsy, many children with unexplained epilepsy do not obtain genetic diagnoses through routine neurological care. This study shows how effective WES conducted for research and clinical purposes in a single institution
We enrolled children with unexplained epilepsy and their family members. WES data were generated for probands and parents and uniformly processed through a standard alignment and variant calling pipeline. Detailed medical history were reviewed by at least two epileptologists according to the 2017 ILAE Seizure and Epilepsy classification. Mendelian inheritance analysis and variant evaluation for pathogenicity prediction was conducted using in silico tools to identify de novo, homozygous, or compound heterozygous variants that were rare. ACMG criteria were annotated to each variant incorporating each patient’s phenotypic information.
We have recruited 502 children with epilepsy and thus far have DNA samples from 299 trios, 172 duos, and 31 probands only. Analyzing 303 cases, we have identified pathogenic/likely pathogenic variants for 56 children with unexplained epilepsy with a range of phenotypes, including generalized epilepsies and focal epilepsies, with and without intellectual disability. We identified 43 missense or splice-affecting de novo variants in genes associated with autosomal dominant conditions and two in the X-linked genes. We identified 11 biallelic variants. Candidate findings in an additional 98 cases require further confirmation and additional case identification before clinical return of results will be pursued.

Our results emphasize the need to pursue genetic evaluation for children with unexplained epilepsy. In our case, an institutional effort allowed us to narrow the gap between research and clinical sequencing.

Authors/Disclosures
Hyunyong Koh, MD, PhD (Texas Children's Hospital)
PRESENTER 		Dr. Koh has nothing to disclose.
No disclosure on file
No disclosure on file
Nitish Chourasia, MD Dr. Chourasia has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
Christelle M. Achkar, MD Dr. Achkar has nothing to disclose.
Heather E. Olson, MD (Boston Children's Hospital Peabody) Dr. Olson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda pharmaceuticals. The institution of Dr. Olson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ovid Therapeutics. The institution of Dr. Olson has received research support from NINDS. The institution of Dr. Olson has received research support from International Foundation for CDKL5 Research. The institution of Dr. Olson has received research support from Marinus Pharmaceuticals. The institution of Dr. Olson has received research support from Ovid Therapeutics.
No disclosure on file
No disclosure on file
Annapurna Poduri, MD, MPH An immediate family member of Dr. Poduri has received personal compensation for serving as an employee of Beam Therapeutics. An immediate family member of Dr. Poduri has stock in Beam Therapeutics. The institution of Dr. Poduri has received research support from NIH.