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

ADAMTS13

Interactive database of 385 literature-reported variants of the ADAMTS13 gene, annotated with multiple in silico tools for coding variants and with AlphaGenome for non-coding variants

Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by pathogenic variants in the ADAMTS13 gene; despite the continual expansion of genetic data, there is still no comprehensive, accessible database of ADAMTS13 variation available for clinicians and researchers. The authors performed a comprehensive literature review and identified 385 ADAMTS13 variants reported in patients worldwide, which they incorporated into an accessible online database documenting the genetic change, variant type and effect, clinical features and population allele frequency. Multiple in silico annotation tools were used to assess coding variation, while AlphaGenome was applied to predict the effects of non-coding variation. Variants were distributed throughout the gene, with significant enrichment in the metalloprotease domain; N-terminal variants were associated with earlier symptom onset and lower residual ADAMTS13 activity, extending previous genotype-phenotype observations to a larger and more diverse collection of variants. The authors conclude that cTTP is molecularly heterogeneous and provide a curated and expandable resource to support variant interpretation, research and clinical practice.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A single access point to the 385 variants, with allele frequency, in silico predictions and clinical features, fills a gap the authors themselves describe, and the association of N-terminal variants with earlier onset and lower residual activity is the most useful finding for genetic counselling. It is, however, a compilation of published cases, hence exposed to the reporting biases of the literature, and the abstract measures neither the performance of the in silico predictions nor the effect of the database on variant classification. For exome or genome interpretation, its value will depend on how it is maintained over time, which the abstract does not detail.

Analysis by Dr Thibaut Benquey