Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura

Abstract

Objective: Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy. The present study aimed to investigate the genes and variants associated with TTP in a Chinese population.

Methods: Target sequencing was performed on 220 genes related to complements, coagulation factors, platelets, fibrinolytic, endothelial, inflammatory, and anticoagulation systems in 207 TTP patients and 574 controls. Subsequently, logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene. Moreover, the associations between common variants and TTP were also investigated.

Results: ADAMTS13 was the only TTP-associated gene (OR = 3.77; 95% CI: 1.82-7.81; P=3.6×10^ȡ4) containing rare deleterious variants in TTP patients. Among these 8 variants, 5 novel rare variants that might contribute to TTP were identified, including rs200594025, rs782492477, c.T1928G (p.I643S), c.3336_3361del (p.Q1114Afs*20), and c.3469_3470del (p.A1158Sfs*17). No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing.

Conclusion: ADAMTS13 is the primary gene related to TTP. The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.

Keywords: ADAMTS13; target sequencing; thrombotic thrombocytopenia purpura.