Abstract Details

Title A Novel Multiple Sclerosis Susceptibility Variant in GRAMD1B Gene

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 136

Objective

Background BACKGROUND: While the role of common genetic variants is clearly established from recent studies on sporadic cases, the contribution of rare variants to the susceptibility of MS in multiplex families remains unclear.

Design/Methods DESIGN/METHODS: A combination of microarray genotyping on the whole family and whole-genome sequencing in 4 MS affected and 4 unaffected individuals belonging to an Italian multiplex family descending from a first cousin marriage has been performed. Linkage analysis was performed using the Merlin software, and SNPeff version 3.0 software used to prioritize rare variants.

Results RESULTS: We identified 437 variants with high functional impact, which narrowed to 208 present with at least one copy in all the patients and to 53 if novel or rare. Two of them were present under one of the two LOD peaks at chromosome 8 and 11. The first one maps to the OR8G5 gene, which is an olfactory receptor gene under positive selection (GERP score=-3.4), while the second falls within the GRAMD1B gene, causing an aminoacid substitution (S601P). This second variant was not present in dbSNP and in the 1,000 Genome project, and it segregates well within the family being homozygote in 3 affected individuals and heterozygote in 1. Sanger sequencing confirmed the above segregation with the disease. GRAMD1B gene is very conserved from yeast to human, it encodes a membrane protein, which is part of the GRAM containing domain family protein, and it is highly expressed in the CNS and in specific immune subtypes like dendritic cells and neutrophils.

Conclusions CONCLUSIONS: Sequencing of a multiplex family has been successful in identifying novel rare genetic variants. Ongoing studies are exploring the role of the mutation on the protein function and the role of the protein in the MS disease ethiopathogenesis.

Authors/Disclosures
Filippo Martinelli Boneschi PRESENTER	No disclosure on file
Federica Esposito	Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Merck. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Federica Esposito has received research support from Italian MS Society. The institution of Federica Esposito has received research support from Italian Ministry of Health. The institution of Federica Esposito has received research support from ERA Net. The institution of Federica Esposito has received research support from European Commission. Federica Esposito has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Melissa Sorosina	Melissa Sorosina has received research support from Italian Multiple Sclerosis Foundation. Melissa Sorosina has received research support from Italian Ministry of Health.
	No disclosure on file
	No disclosure on file
Francesco Patti, MD	Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Almirall. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Meyers. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson and Johnson. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. The institution of Dr. Patti has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Almirall, Bayer, Biogen, Bristol Meyers and Squibb Merck, Roche, Sanofi, TEVA. Dr. Patti has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for University of Catania and AISM/FISM, Fondazione Italiana Sclerosi Multipla. Dr. Patti has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology.
	No disclosure on file
	No disclosure on file
Ruggero Capra, MD	Dr. Capra has nothing to disclose.
	No disclosure on file
Giancarlo Comi, MD (University Vita-Salute)	Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Aspen Healthcare. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sanofi. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Rewind.

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