Genotyp-Phenotype Correlation in Congenital ADAMTS13 Deficient Patients
Authors: Lotta Luca Andrea , Garagiola Isabella , Cairo Andrea , Klaassen Robert , Metin Ayse , Gurgey Aytemiz , Peyvandi Flora 
Published: April 2020

Abstract
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia. Congenital TTP is associated with the plasma deficiency of von Willebrand factor-cleaving protease (ADAMTS13) due to mutations in the corresponding gene. To date 75 patients with congenital ADAMTS13 deficiency and more than 70 mutations of ADAMTS13, responsible for congenital TTP, have been reported in the literature, but a clear genotype-phenotype correlation is not established.
STUDY: In order to evaluate genotype-phenotype correlation, we have cumulated laboratory (genetic analysis and plasma ADAMTS13 activity) and clinical data on 8 unrelated congenital TTP families from our TTP database (http://www.ttpdatabase.org) with data stemming from previously published studies (75 patients with congenital ADAMTS13 deficiency).
RESULTS: Disease onset, defined as the age of the first episode, was used to classify patients’ severity phenotype. Of 79 patients with ADAMTS13 deficiency and available information on disease onset, 47% (n=37) had a neonatal onset, 32% (n=25) an intermediate (2 months-18 years) and 16% (n=13) an adult onset (&gt;18 years). In addition, 5% (n=4) of the ADAMTS13-deficiency patients reached the adult age without developing episodes of TTP. Analysis of data on ADAMTS13 genotypes highlighted a clear influence of genotype on age of disease onset (Figure 1). The two most frequently reported ADAMTS13 mutations (4143_4144insA, n=16; R1060W, n=9) were associated with different age of onset: patients carrying the R1060W mutation always showed an adult onset, while only one patient carrying 4143_4144insA mutation reached the adult age without developing TTP. On the basis of the published results on in vitro expression studies, ADAMTS13 mutations were arbitrarily classified in two categories (the list of mutations is not reported in the abstract): group of mutations that conserve secretion and catalytic activity of the recombinant ADAMTS13 protein (called A13+) and group of mutations with a complete abolition of secretion and/or catalytic activity of ADAMTS13 (called A13-). We hypothesized that carriers of A13+ mutations could be protected from early onset of the disease. Therefore we divided patients with congenital deficiency (n=79) in two groups: Group A (n=27), carriers of one of A13+ mutations and Group B (n=52), non-carriers of the latter mutations. Kaplan-Meier survival curves were plotted and a log-rank test, performed to compare disease-free survival of the two groups (Figure 2), showed a significant difference in disease-free survival between the two groups (chi-square= 9,971; g.f.=1; p=0.002). Patients homozygous for A13- genotype showed a neonatal onset.
CONCLUSIONS: Our results support the hypothesis that ADAMTS13 genotype influences the time of onset of congenital TTP by determining different patterns of ADAMTS13 plasma levels in patients. However, it was not possible to establish a direct correlation between genotype and plasma levels of ADAMTS13 activity, owing to the heterogeneous information available from different studies and lack of sensitivity of current ADAMTS13 activity assays, when very low levels of ADAMTS13 activity are measured. Further studies with more sensitive and standardized ADAMTS13 assay are needed to confirm that patients with late-onset disease do conserve higher levels of ADAMTS13 activity as compared to early-onset disease patients and to establish the clinical and therapeutical implications of our findings.
Figure 1. Age of onset of TTP in patients with different ADAMTS13 genotypes (A–K). Figure 1. Age of onset of TTP in patients with different ADAMTS13 genotypes (A–K). Figure 2. Figure 2.