ADAMTS13 was first reported in relation to autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura (TTP) in 2001 (Levy et al., PMID: 11586351). TTP is characterized by a deficiency of ADAMTS13 which may be congenital/familial due to inherited variants in the ADAMTS13 gene (also called Upshaw-Shulman syndrome) or acquired due to autoantibodies against ADAMTS13. ADAMTS13 cleaves ultra large von Willebrand Factor multimers into smaller multimers, rendering them less adhesive to platelets, preventing thrombosis. Genetic modifiers and environmental triggers are reported to play a role in the disease onset and severity. At least 175 ADAMTS13 variants, ranging from missense, in-frame indel to nonsense, frameshifts have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of case level data (12 points): Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs 11586351, 17003922, 19055667, 12393505). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached.
The mechanism for disease is loss of function (PMID: 11586351, 28416507, 27505881).
Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays (PMID: 12775718, 17003922). Many attempts at recapitulating the disease phenotype in mice have been made and was achieved with the injection of ultralarge VWF multimers as a trigger (PMID: 22529289). Rescue evidence in mouse is also available (PMID: 28254814, 22529289).
In summary, ADAMTS13 is definitively associated with autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on March 25, 2020 (SOP Version 6).
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