Global Prevalence of Hereditary Thrombotic Thrombocytopenic Purpura Determined by Genetic Analysis

• ADAMTS13 exome/genome data from 807,162 gnomAD population was analyzed to establish worldwide/within-population prevalence of hereditary TTP

• Hereditary TTP prevalence is substantially higher than currently estimated, suggesting that many hereditary TTP patients are not diagnosed

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare autosomal recessive, life-threatening disorder caused by a severe deficiency of the plasma enzyme, ADAMTS13. The current estimated prevalence of hTTP in different regions of the world, 0.5-2.0 patients/million, is determined by the frequency of diagnosed patients. To evaluate more accurately the worldwide prevalence of hTTP, and also the prevalence within distinct ethnic groups, we used data available in exome and genome sequencing of 807,162 (730,947 exomes, 76,215 genomes) subjects reported recently by the Genome Aggregation Database (gnomAD-v4.1). Among 1,614,324 analyzed alleles in the gnomAD population we identified 6,321 distinct ADAMTS13 variants. Of these 6,321 variants, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). 10,154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7,759 (77%) with previously reported variants. Considering all 758 pathogenic variants and also only the 140 previously reported variants, we estimated a global hTTP prevalence of 40 and 23 cases/106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42/106). The estimated prevalences of other populations were: Finnish, 32/106; non-Finnish Europeans, 28/106; Admixed Americans, 19/106; Africans/African Americans, 6/106; and South Asians, 4/106. The lowest prevalences were Middle Eastern, 1/106 and Ashkenazi Jews, 0.7/106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many hTTP patients may not be diagnosed or may have died during the neonatal period.