Abstract
Low-frequency candidates for susceptibility to thromboangiitis obliterans (TAO) were investigated by whole exome sequencing in a family with a young member with migrating thrombophlebitis, artery thrombosis, and ulcerations followed by below-knee amputation. Filtering among 193 candidates for venous thromboembolism (VTE) detected rare heterozygous variants: the PPIF (peptidylprolyl-isomerase F) frameshift p.Tyr121fs*0 [minor allele frequency (MAF)= 0.000004], the F2 (thrombin) synonymous/splicing p.Gly271=, and 5 missense variants. Among these, the novel PTGIR (prostaglandin I2 receptor) p.Tyr144Asn would interfere with transmembrane helix interaction, and potentially decrease prostacyclin response. Filtering among 92 genes, suggested by previous genomic and transcriptomic studies in TAO patients, detected a rare combination of HLA-DQB1 alleles, and two in linkage variants (MAF=0.0003) in titin (TTN). Interestingly, TTN is also reported among VTE proteome alterations. By exploring the whole exome, the novel BET1 nonsense p.Glu33Ter change may indirectly influence hemostasis and endothelial integrity. This study pinpoints novel TAO candidate genetic components for further investigation