Abstract Details

Title Lack of Low-Frequency Complete-Penetrance Coding Variants Responsible from Familial Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 15-072

Objective The aim of the study was to identify rare high-penetrance risk variants for multiple sclerosis (MS).

Background More than 230 common genetic variants with low-to-moderate effects have been identified for MS, which together can explain less than half of the predicted MS heritability. We hypothesised that shared rare, homozygous risk variants within affected individuals of multiplex MS families with multiple parental consanguinities may explain a fraction of the missing heritability.

Design/Methods A total of 43 individuals in seven families with three-to-five MS patients and their healthy relatives were included in the study. Following SNP genotyping (710K/2.5M, Illumina), linkage analysis under recessive model and homozygosity mapping were performed for each family. Exome sequencing was done for one-to-three individuals from each family to determine candidate pathological variants within the candidate linked and homozygous chromosomal regions.

Results Maximum LOD scores yielded from the linkage analyses varied between 1.33 and 2.10. No rare homozygous variants with complete penetrance were detected on the candidate regions. Moreover, previously reported rare risk variants for MS did not segregate in the studied families. We detected a number of rare incomplete-penetrance variants, some of which are located on the following genes; CLEC18C (rs62052576), CYP2D7 (rs774572059), UGT2B17 (rs555824070), ZGPAT (c.C550A, p.L184M), GOLGA4 (c.A3185G, p.H1062R), TTC21A (rs201536754), RP1L1 (c.G6856C, p.D2286H; c.C3167T, p.A1056V; c.T926G, p.M309R), C1GALT1C1 (rs758199720), CTAGE4 (c.*57G>A).

Conclusions We did not detect complete-penetrance disease-causing variants in the studied seven MS families. Given that the most known MS risk alleles do not fall within the gene-coding regions, genome sequencing in those families with increased recurrence risks may reveal non-coding risk variants involved in regulatory mechanisms. In addition, detected rare variants may contribute to increased susceptibility within individual families, which require further investigation in terms of frequency and familial segregation coupled with clinical re-evaluation.

Authors/Disclosures
Aksel Siva, MD (Istanbul University Cerrahpasa School of Medicine) PRESENTER	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.
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.
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.
Melih Tutuncu, MD (ISTANBUL UNIVERSITESI CERRAHPASA TIP FAKULTESI)	Dr. Tutuncu has nothing to disclose.
Sabahattin Saip	Sabahattin Saip has nothing to disclose.
Taskin Duman (Flukara Numune Hospital)	Dr. Duman has nothing to disclose.
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 .

��ɫ��

��ɫ��