PB0312 - A novel ADAMTS13 variant found in a patient with Congenital Thrombotic Thrombocytopenic Purpura

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a rare thrombotic microangiopathy caused by reduced ADAMTS13 activity. Most TTP is immune mediated, however congenital TTP (cTTP) represents a minority of presentations. Here we present a novel ADAMTS13 variant in a 24-year-old indigenous Australian female with cTTP diagnosed during pregnancy. cTTP is an autosomal recessive disorder with over 100 mutations described.

Aims: To investigate the genetic mutations in a case of cTTP.

Methods: Whole genome sequencing (WGS) was performed at Victorian Clinical Genetics Services.

Results: The patient presented in first pregnancy at 23 weeks gestation with clinical features of TTP. ADAMTS13 activity was 5.5% and there was no inhibitory antibody identified. The patient improved with TTP therapy which included plasma exchange, however the fetus did not survive.
WGS demonstrated two compelling ADAMTS13 variants for her phenotype; NM_139025.4:c.3178C>T;p.(Arg1060Trp) and c.725G>A;p.(Cys242Tyr). The Arg1060Trp is a known pathogenic variant in the setting of cTTP, it is associated with later disease onset and often with first presentation during pregnancy. The Cys242Tyr variant occurs in the pre-spacer region and is absent from healthy population databases (gnomAD). This report is the first time this variant has been described in a patient and so it is classified as a suspicious variant of uncertain significance. Pre-spacer mutations are reported as being associated with earlier age of symptom onset. Familial testing is underway to inform the risk to this patient’s siblings. The patient is undergoing therapy with prophylactic plasma infusions and has been counselled that she will able to attempt future pregnancy with close hematological monitoring and plasma support.

Conclusion(s): Here we describe cTTP occurring due to compound heterozygous ADAMTS13 variants including a novel variant c.725G>A;p.(Cys242Tyr) not previously reported. These findings contribute to the understanding of the genomic landscape of cTTP and permit optimized care for this patient and her family.