An Interactive Database of ADAMTS13 Variants Yields Novel Insight into Thrombotic Thrombocytopenic Purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by pathogenic variants in ADAMTS13. Despite the continual expansion of genetic data, there remains no comprehensive, accessible database of ADAMTS13 variation available for clinicians and researchers. We performed a comprehensive literature review and identified 385 ADAMTS13 variants reported in patients worldwide, which were incorporated into an accessible online database to help address this unmet need. Within our database, there is information included on the genetic changes, variant type and effect, clinical features and population allele frequency, to give a thorough and detailed assessment of the variation seen in ADAMTS13. Multiple in silico annotation tools were used to assess coding variation, while AlphaGenome was applied to predict effects of non-coding variation. Variants were distributed throughout the gene, with significant enrichment of variants within the metalloprotease domain. N-terminal variants were associated with earlier age of symptom onset and lower residual ADAMTS13 activity, extending previous genotype-phenotype observations to a larger and more diverse collection of variants. Overall, these findings demonstrate the molecular heterogeneity in cTTP and provide a curated and expandable resource to support variant interpretation, future research, and clinical practice.