Abstract Details

Title Exome-sequencing of Turkish Families with Multiple Sclerosis: Low Frequency and Rare Variant Contributions into Susceptibility

Topic Multiple Sclerosis

Presentation(s) P10 - Poster Session 10 (5:00 PM-6:00 PM)

Poster/Presentation
Number 1-002

Objective Multiple sclerosis (MS) is characterized as an immune-mediated central nervous system disease marked by chronic inflammation, demyelination, and progressive neurodegeneration.

Background In this study, we evaluated the contribution of low-frequency and rare genetic variants to MS susceptibility within one of the largest family-based MS cohorts to date, comprising 215 individuals from 60 Turkish multiplex MS families.

Design/Methods Whole exome sequencing was conducted on all 215 samples including affected and unaffected members, followed by investigating the effect of well-established HLA loci for MS on the elevated MS risk observed in our families. To prioritize the genes and pathways that are potentially associated with MS, a segregation-based analysis of the variants was conducted and complemented by gene-based pathway enrichment analysis. Subsequently, a gene-based burden analysis was performed on candidate genes identified through both our segregation analysis and existing literature.

Results

Our results highlighted the significance of the extracellular matrix in MS pathogenesis, as we identified laminin-related genes including LAMA5 and LAMB1 from both the segregation analysis as well as from the gene-based burden test. Hemidesmosome assembly emerged as a key pathway in our analysis, primarily driven by the identification of DST and PLEC as significant genes in the gene-based segregation analysis. Finally, we identified two rare coding variants passing our allele frequency and deleteriousness score based filters, rs41266745 (C>T) in the CD109 gene and rs143093165 (T>G) in the ITPR1 gene which is pLI 1.00 and LOEUF 0.325, completely segregating within more than one families.

Conclusions

This is one of the first and largest family-based MS studies from Turkey that features a unique cohort that can potentially enable the detection of novel low-frequency and rare variants associated with MS. The findings from this study offer valuable insights that could guide future research aimed at further exploring and understanding the factors contributing to MS risk.

Authors/Disclosures
Furkan Büyükgöl (Acibadem University) PRESENTER	Furkan Büyükgöl has nothing to disclose.
Berk Gürdamar (Department of Biostatistics and Bioinformatics, Graduate School of Health Sciences, Acibadem University, Istanbul, Türkiye)	No disclosure on file
Alper Bulbul	Alper Bulbul has nothing to disclose.
Osman Ugur Sezerman, PhD	Prof. Sezerman has nothing to disclose.
Elif Everest, PhD (National Institutes of Health)	Ms. Everest has received personal compensation in the range of $50,000-$99,999 for serving as a postdoctoral visiting fellow with National Institutes of Health.
Umut Voyvoda (Acibadem University)	Umut Voyvoda has nothing to disclose.
Meziyet D. Reda, Master Of Science Student	Miss Reda has nothing to disclose.
özge çetin (Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences Acibadem University, Istanbul, Türkiye)	No disclosure on file
Meryem A. Tuncer, MD (Turkiye Klinikleri)	Dr. Tuncer has nothing to disclose.
Bedriye Karaman, MD	Dr. karaman has nothing to disclose.
beril tasdelen (Clinic of Neurology, Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul, Türkiye)	No disclosure on file
Caner Feyzi Demir	Caner Feyzi Demirkaya has nothing to disclose.
Cavit Boz, MD	Dr. Boz has nothing to disclose.
Cihat Uzunkopru (Katip Celebi Univ. Atatürk EAH)	Cihat Uzunkopru has nothing to disclose.
gülgün uncu (Department of Neurology, Eskisehir City Hospital, Eskisehir, Türkiye)	No disclosure on file
Haluk Gumus	Haluk Gumus has nothing to disclose.
Husnu Efendi, MD (Gen Pharmacenticals)	The institution of Dr. Efendi has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Alexion. The institution of Dr. Efendi has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sanofi. The institution of Dr. Efendi has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Roche. The institution of Dr. Efendi has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Novartis.
Mehmet Fatih Yetkin (Erciyes university)	Mehmet Fatih Yetkin has nothing to disclose.
Mehmet Tecellioglu	No disclosure on file
Meral Seferoglu	No disclosure on file
Murat Kurtuncu, MD (Istanbul University)	Dr. Kurtuncu has nothing to disclose.
Murat Terzi, PhD (19 Mayis Universitesi)	Dr. Terzi has nothing to disclose.
Muzaffer Mutluer	Dr. Mutluer has nothing to disclose.
Ayse Nur Yuceyar, MD	No disclosure on file
Omer F. Turan, MD	Dr. Turan has nothing to disclose.
Ozlem Ethemoglu	No disclosure on file
Rana Karabudak, MD (Academic Neurologist)	Dr. Karabudak has nothing to disclose.
Sena Destan Bunul	Sena Destan Bunul has nothing to disclose.
Sedat Sen	No disclosure on file
Serkan Demir, MD (DR.ILHAN VARANK HASTANESI)	Dr. Demir has nothing to disclose.
Taskin Duman (Flukara Numune Hospital)	Dr. Duman has nothing to disclose.
Tuncay Gunduz, MD (ISTANBUL UNIVERSITESI NOROLOJI SERVISI)	The institution of Dr. Gunduz has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Pharmaceuticals. Dr. Gunduz has received research support from Turkish Neuroimmunology Society.
Ufuk Aluclu, PhD	No disclosure on file
Yesim Beckmann, MD (GenPharmaceuticals)	Dr. Beckmann has nothing to disclose.
Kaya Bilguvar, MD, MBBS, PhD	Dr. Bilguvar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global Advisors. The institution of Dr. Bilguvar has received research support from NIH. The institution of Dr. Bilguvar has received research support from TUBITAK. Dr. Bilguvar has received intellectual property interests from a discovery or technology relating to health care. Dr. Bilguvar has received publishing royalties from a publication relating to health care. Dr. Bilguvar has received personal compensation in the range of $500-$4,999 for serving as a Grant Reviewer with NIH.
Bade Gulec	Bade Gulec has nothing to disclose.
Melih Tutuncu, MD (ISTANBUL UNIVERSITESI CERRAHPASA TIP FAKULTESI)	Dr. Tutuncu has nothing to disclose.
Ugur Uygunoglu (Cerrahpasa)	Ugur Uygunoglu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Turkey . The institution of Ugur Uygunoglu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Ugur Uygunoglu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen Idec/Gen Pharma of Turkey. The institution of Ugur Uygunoglu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck-Serono of Turkey. The institution of Ugur Uygunoglu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanovel of Turkey. The institution of Ugur Uygunoglu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Genveon of Turkey.
Sabahattin Saip	Sabahattin Saip has nothing to disclose.
Aksel Siva, MD (Istanbul University Cerrahpasa School of Medicine)	Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen - TR. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ali Raif Pharmaceuticals, Turkiye. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanovel Pharmaceuticals, Turkiye. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abdi Ibrahim Ilac - TR. Dr. Siva has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono . The institution of Dr. Siva has received research support from Turkish MS Society. The institution of Dr. Siva has received research support from The Scientific and Technological Research Council Of Turkey - Health Sciences Research Grants.
Eda Turanli	The institution of Eda Turanli has received research support from Scientific and Technological Research Council of Turkey (TÜBITAK). The institution of Eda Turanli has received research support from Turkish MS Society. The institution of Eda Turanli has received research support from Acibadem University Scientific Research Projects Commission . The institution of Eda Turanli has received research support from Istanbul University Scientific Research Projects Commission .

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