THU0024 Whole genome linkage and exome sequencing analyses in an autosomal recessive takayasu arteritis family

Abstract

Background Takayasu arteritis (TA) is a rare chronic inflammatory disease of the aorta and its major branches, seen predominantly in females. Its etiology is unknown, however, there is a growing body of evidence to suggest genetic contribution to the pathogenesis of the disease: a) The disease is relatively frequent in Asia, b) Several familial cases of TA have been published (1) and even, autosomal recessive inheritance pattern has been suggested (2), c) Genetic association with HLA-B*52 across multiple ethnicities has been confirmed (3), and d) A multi-ethnic genome-wide association studies (GWAS) study in TA established additional genetic susceptibility loci (4–5). Objectives We studied a consanguineous family consisting of two affected and one unaffected sibs and their healthy parents in order to identify the causative mutation or linked loci. Methods Whole genome single nucleotide polymorphism (SNP) genotyping was performed for five family members using Illumina OmniExpress-24 BeadChip targeting ∼700,000 SNP markers. Using genotyping data, we performed multipoint parametric linkage analysis assuming recessive inheritance and complete penetrance. Also, exome sequencing was performed for index patient to search for a rare, homozygous deleterious variant in the possibly linking regions. Results Whole-genome linkage analysis resulted in 25 genomic regions with LOD score above 1.50. Within the family members, all candidate regions shared homozygosity by only affected individuals. Causative variant search in linkage regions identified seven homozygous candidate variants in which five of them were located in 19q13.33. Candidate non-synonymous variants were found in ANXA8L, EHBP1L1, MYH14, KCNJ14, SYNGR4, TULP2 and SHANK1 genes. Conclusions This is the first whole genome linkage analysis in a TA family with recessive inheritance. Linkage and following exome sequencing analyses revealed seven possible variants that may be causative to disease. Further variant and candidate gene investigations are still in process. References Morishita KA, et al. Familial Takayasu arteritis – a pediatric case and a review of the literature. Pediatr Rheumatol Online J. 2011 Feb 2;9:6. Jeeva I, et al. Atypical Takayasu arteritis: a family with five affected siblings. Med Sci Monit. 2007 Aug;13(8):CS101–5. Sahin Z et al. Takayasu9s arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey. Arthritis Res Ther. 2012 Feb 6;14(1):R27. Renauer PA et al. Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study. Arthritis Rheumatol. 2015 May;67(5):1361–8. Saruhan-Direskeneli G,. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am J Hum Genet. 2013 Aug 8;93(2):298–305. Disclosure of Interest None declared