PB0300 - Estimating the population-based prevalence of congenital TTP using 807,162 exome and genome sequencing from gnomAD

Background: Congenital thrombotic thrombocytopenic purpura(cTTP) is a rare autosomal-recessive and life-threatening disorder resulting from ADAMTS13 mutations. The population prevalence of cTTP is unknown, with estimates ranging from 0.5-16.7 cases/million people.

Aims: To estimate the worldwide and within-population prevalence of cTTP using sequencing data from the Genome Aggregation Database(gnomAD).

Methods: Exome and genome sequencing data of 807,162 subjects from gnomAD-V4 were extracted and analyzed for ADAMTS13. Obtained results were compared to 302 ADAMTS13 variants reported in the literature, Human-Gene-Mutation-Database(HGMD) and Leiden-Open-Variation-Database(LOVD) causing cTTP. The following gnomAD variants were considered pathogenic: variants associated with cTTP in HGMD/LOVD; nonsense and frameshift; splicing variants affecting the first/last two intronic nucleotides; variants affecting the first/last eight intronic nucleotides, inframe and missense variants predicted deleterious by 4, 3 and 7 in-silico tools, respectively.

Results: We identified 6,321 variants within ADAMTS13 in gnomAD among 1,614,324 analyzed alleles. Of these, 758 different variants were pathogenic; 118 previously reported in cTTP and 640 predicted to be pathogenic. Among 1,614,324 analyzed alleles, 10,154 were affected by the aforementioned variants(7,509-reported and 2,645-novel). Seventeen subjects were homozygous for pathogenic variants(15 with reported and 2 with novel variants). Considering all pathogenic variants(n=758) and only those reported(n=118), we estimated an overall cTTP prevalence of 40 and 22 individuals per million people, respectively(Table 1). The prevalence of cTTP per million people using reported variants only was 5 in Africans/African Americans, 19 in Admixed Americans, 0.7 in Ashkenazi Jews, 39 in East Asians, 30 in Finns, 26 in Europeans, 1 in Middle Eastern and 4 in South Asians.

Conclusion(s): We newly estimated the worldwide and within-population cTTP prevalence by using 807,162 genome/exome sequencing data and identified 640 novel variants in addition to the 302 previously reported. Our results reveal that putative disease alleles and cTTP-associated variants are more prevalent than expected, suggesting that a large number of patients might be undiagnosed.