Thrombotic Thrombocytopenic Purpura (TTP) via the ADAMTS13 Gene

Thrombotic thrombocytopenic purpura (TTP) (OMIM 274150), often described as Upshaw-Schulman syndrome (USS), is a rare blood condition characterized by frequent relapses of fever, hemolytic anemia, thrombocytopenic purpura, neurologic symptoms, renal disease, and possible organ failure. TTP is caused by variants in the ADAMTS13 gene (Levy et al. Nature 413:488-494, 2001) and differs from the more common autoimmune disease known as idiopathic or immune thrombocytopenic purpura (ITP). TTP preferentially affects the microvasculature of the brain and kidneys. Initial symptoms may include hypertension, headache, numbness or transient paralysis, confusion, and difficulty speaking. In a related disorder, hemolytic uremic syndrome (HUS), neurologic symptoms are less common, while renal failure is more predominant. In unaffected individuals, large multimers of the platelet-adhesive protein von Willebrand factor (vWF) are secreted from platelet stores into blood plasma where they are cleaved by the metalloprotease ADAMTS13 during a key step of thrombosis (Furlan et al. Blood 87:4223-4234, 1996). In patients with TTP, cleavage of vWF multimers is diminished or absent due to either loss-of-function variants in ADAMTS13 or to lack of ADAMTS13 secretion from storage granules in platelets and megakaryocytes (Mannucci et al. Blood 74:978-983, 1989; Kokame et al. Proc. Natl. Acad. Sci. U.S.A. 99:11902-11907, 2002). Deficiencies in vWF cleavage result in the formation of damaging microvascular thrombi, comprising platelets and vWF multimers, that cause erythrocyte lysis and other symptoms of TTP (Moake et al. N. Engl. J. Med. 307:1432-1435, 1982). TTP affects males and females equally and may present at any age. Without preventative treatment, episodes of TTP typically recur every 21 to 28 days and are often precipitated by other stressors including infection, surgery, or pregnancy (Furlan and Lämmle. Best Pract Res Clin Haematol. 14:437-454, 2001).

Variants in ADAMTS13 are inherited in an autosomal recessive manner, although individuals heterozygous for pathogenic variants often display mild deficiencies of ADAMTS13 activity (Levy et al. Nature 413:488-494, 2001; Kokame et al. Proc. Natl. Acad. Sci. U.S.A. 99:11902-11907, 2002). Causative variants in ADAMTS13 have been identified throughout the coding sequence. No predominant ADAMTS13 variants have been identified, but the phenotypes resulting from secretion-deficient ADAMTS13 variants appear to be more severe than the phenotypes resulting from secreted ADAMTS13 with diminished function (Kokame et al. Proc. Natl. Acad. Sci. U.S.A. 99:11902-11907, 2002).

Variants in ADAMTS13 account for nearly 100% of cases of congenital TTP.

This test provides full coverage of all coding exons of the ADAMTS13 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).