THU0005 Whole genome linkage and exome sequencing analyses in takayasu arteritis families

• Published in: Annals of the rheumatic diseases Vol. 77; no. Suppl 2; p. 231
• Main Authors: Tahir Turanlı, E., Karacan, I., Esatlioglu, S.N., Sahin, S., Kasapcopur, O., Tolun, A., Seyahi, E.
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.06.2018
• Subjects: Aorta; Arteritis; Arthralgia; Benign; Etiology; Families & family life; Fever; Fibrosis; Genomes; Genotyping; Heredity; Inflammation; Linkage analysis; Mutation; Single-nucleotide polymorphism; Takayasu's disease; Vasculitis; Vein & artery diseases
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2018-eular.6749

BackgroundTakayasu arteritis (TA) is an inflammatory large vessel vasculitis affecting mainly aorta and its branches. Inflammation in vessels causes thickening of walls, fibrosis, dilatation and nonspecific symptoms such as fever, hypertension and arthralgia. It is a rare disorder with unknown etiology and the worldwide incidence is 0.4 to 2.6 per million.ObjectivesWe studied three consanguineous families with consisting of two affected daughters each and their healthy parents in order to identify the disease locus and the causative mutationMethodsIn two of the families, genome-wide single nucleotide polymorphism (SNP) genotyping was performed for available 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 four of the patients to search for rare, homozygous deleterious variants. For TA1 and TA2 families whether the variants were located in a region IBD (identical by descent) in affected sisters or not was investigated.ResultsWhole genome linkage and exome analyses identified homozygous, rare (MAF <0.01) candidate variants shared by the affected sister pairs in the first two families. Candidate variants for the first family were in ANXA8L1, EHBP1L1, TULP2, MYH14 and SHANK1 and for the second family in AP4B1, RIMBP3, VCX3B and NXF2. In the third family, no candidate homozygous variant was common for the affected sibs, who had different fathers. In silico functional predictions of the candidate variants shared by each sister-pair were determined.Abstract THU0005 – Table 1In silico functional predictions of candidate variantsFamilyGeneChangeSIFTPolyPhen2MutationTaster TA1ANXA8L1c.449C>T (p.T150M)DeleteriousProbably damagingDisease CausingEHBP1L1c.3595C>T(p.R1199C)DeleteriousProbably damagingPolymorphismTULP2c.1300T>C(p.Y434H)ToleratedBenignPolymorphismMYH14c.565C>T(p.R189C)DeleteriousProbably damagingDisease CausingSHANK1c.3947G>A(p.G1316D)ToleratedPossibly damagingDisease CausingTA2AP4B1c.263C>T (p.T88I)ToleratedBenignDisease CausingRIMBP3c.3788A>C (p.E1263A)ToleratedBenignPolymorphismVCX3Bc.44A>G (p.K15R)ToleratedPossibly damagingPolymorphismNXF2c.1301+1G>A--Disease CausingConclusionsThis is the first whole genome linkage analysis and subsequent exome sequencing in TA patients with suggestive recessive inheritance. Possible candidate variants in two out of the three families were determined. However, we could not find any genetic change in terms of genetic mutations, exonic deletions or structural variations shared by these families. We had hoped that the study in these rare families with a pair of TA sibs would unravel a gene responsible for TA. We now question whether the inheritance is dominant with reduced penetrance which requires more familial cases to be studied.AcknowledgementsThis study was supported by TÜBıTAK (Grant No 114Z829).Disclosure of InterestNone declared