Abstract Details

Title Whole-Exome Sequencing in Multiplex Families Identifies Novel Rare Variants in Multiple Sclerosis

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 137

Objective

Background BACKGROUND: Multiple sclerosis (MS) has a strong genetic component. Although genome-wide association studies have identified many newly associated genes, less than 50% of the genetic architecture of MS has been explained.

Design/Methods DESIGN/METHODS: We performed whole exome sequencing to scan multiplex families for rare variants using the Agilent 50Mb kit and sequencing on an Illumina HiSeq2000. Variants in 127 individuals from 26 multiplex families were filtered assuming both a dominant and a recessive model. Filtered variants were restricted to high quality coding (nonsense, missense, or splice), conserved, potentially damaging, and rare (minor allele frequency ? 0.01 for a dominant model and minor homozygote frequency ? 0.05 for a recessive model).

Results RESULTS: Nine variants in nine genes segregated completely in at least two families. Six variants that fit a dominant model were genotyped in 8,090 individuals (4,009 controls, 1,762 affected, and 2,319 unaffected from MS families). The strongest association (in C6orf170) trended but was not significant (p=0.066). We identified 28 novel genes having rare variants that segregated completely in at least two families. Four genes (ADAMTSL1, COL11A2, DCHS2, DNAH1) had at least three distinct variants segregating in three different families, and two genes had at least three distinct variants segregating in two families (RECK, TTN). COL11A2 is in the HLA complex and has shown association with outcome prediction of MS, while autoantibodies to TTN are known to be produced in patients with the autoimmune disease scleroderma. While variants in COL11A2 and TTN are segregating in three and two families respectively, a total of 13 families for COL11A2 and 22 families for TTN had at least 1 affected with a filtered variant.

Conclusions CONCLUSIONS: Rare variants in genes previously not associated with MS are likely to play a role in MS risk.

Authors/Disclosures
Jonathan Haines, MD (Vanderbilt University) PRESENTER	No disclosure on file
Ashley Beecham	The institution of Ashley Beecham has received research support from National Multiple Sclerosis Society.
Jacob L. McCauley (University of Miami)	No disclosure on file
Gary R. Cutter, PhD (University of Alabama At Birmingham)	Dr. Cutter has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for onsulting or Advisory Boards: Alexion, Antisense Therapeutics/Percheron, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Endra Life Sciences, Cognito Therapeutics, Genzyme, Genentech, Immunic, Klein-Buendel Incorporated, Kyverna Therapeutics, Inc. , Linical, Merck/Serono, Noema, Neurogenesis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Revelstone Consulting, Roche, SAB Biotherapeutics, Sapience Therapeutics, Scott&Scott LLP, Tenmile.. Dr. Cutter has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Data and Safety Monitoring Boards: Applied Therapeutics, AI therapeutics, AMO Pharma, Argenx, Astra-Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb, CSL Behring, Cynata Therapeutics, DiamedicaTherapeutics, Horizon Pharmaceuticals, Immunic, Inhibrix, Karuna Therapeutics, Kezar Life Sciences, Medtronic, Merck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma Holdings, Prothena Biosciences, Novartis, Pipeline Therapeutics (Contineum), Regeneron, Sanofi-Aventis, Teva Pharmaceuticals, United BioSource LLC, University of Texas Southwestern.. Dr. Cutter has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JASN.
	No disclosure on file
Patrice Whitehead	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)	Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.
Jorge Oksenberg, MD (UCSF)	No disclosure on file
	No disclosure on file
Jeffery Vance, MD, PhD (University of Miami)	Dr. Vance has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for neurology genetics.
Margaret A. Pericak-Vance, PhD (University of Miami Miller School of Medicine)	Dr. Pericak-Vance has nothing to disclose.

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