Global prevalence of hereditary thrombotic thrombocytopenic purpura determined by genetic analysis

Abstract

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 to 2.0 patients per 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 6321 distinct ADAMTS13 variants. Of these, 758 were defined as pathogenic; 140 (18%) variants had been previously reported and 618 (82%) were novel (predicted as pathogenic). In total 10 154 alleles (0.6%) were carrying the reported or predicted pathogenic variants; 7759 (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 per 106, respectively. Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 106). The estimated prevalences of other populations were: Finnish, 32 per 106; non-Finnish Europeans, 28 per 106; Admixed Americans, 19 per 106; Africans/African Americans, 6 per 106; and South Asians, 4 per 106. The lowest prevalences were Middle Eastern, 1 per 106 and Ashkenazi Jews, 0.7 per 106. This population-based genetic epidemiology study reports that hTTP prevalence is substantially higher than the currently estimated prevalence based on diagnosed patients. Many patients with hTTP may not be diagnosed or may have died during the neonatal period.

Graphical abstract

Figure 1.

Flowchart of data analyses. The gnomAD data set includes 807 162 subjects (1 614 324 alleles). Among this population, 6321 distinct ADAMTS13 variants were identified, of which 2525 variants were short insertions/deletions and single-nucleotide variants. We applied our pathogenicity criteria (supplemental Table 2) to identify pathogenic variants among the 2525 variants. Overall, 758 distinct variants were classified as pathogenic; among them, 418 variants (55%) were identified in only 1 individual (ie, were unique). Of these 758 pathogenic ADAMTS13 variants, 140 had been previously reported to cause hTTP and 618 were newly predicted to be pathogenic. A total of 10 154 alleles were carrying these 758 pathogenic variants, 7795 (77%) reported variants and 2359 (23%) predicted variants. Missense variants were the most common form of the pathogenic variants (61%), and they were responsible for the majority of the 10 154 affected alleles by pathogenic variants (92%). A start-lost variant is a point mutation in the ATG start codon, which prevents the original start translation site from being used. A stop-gained is a DNA variant that changes at least 1 base of a codon, leading to a premature stop codon.

Figure 2.

Ethnicity-specific variants that determined the prevalence of hTTP. This figure shows the minor allele frequency (MAF) of the most frequent pathogenic variants identified in gnomAD population among different ethnicities. Variants p.Arg1060Trp, p.Pro457Leu, and p.Asp187His were shared by different populations. The high prevalences of hTTP found in the 3 ethnicities, including East Asians (42 per 10⁶), Finns (32 per 10⁶), and European populations (28 per10⁶) were because of some pathogenic variants that were frequent in these ethnicities. Variant p.Gln723Lys was remarkably frequent among East Asians; p.Pro457Leu and p.Arg1060Trp in Finns; and variants p.Pro457Leu, p.Arg1060Trp, p.Asp187His, and c.4143dup in non-Finnish European population.

Figure 3.

Evaluation of the severity of variants’ pathogenicity. We used a combined annotation dependent depletion score (CADD), a tool for scoring the deleteriousness of genetic variants, with cutoff of >20 to determine the effect of variant severity, among the 3 genetic variants categories. They were including predicted variants (n = 618), previously reported variants that were identified in gnomAD (n = 140), and the 153 variants that have been reported to cause hTTP in the literature but were not found in gnomAD. This figure also shows the distribution of the CADD score among them, with no significant differences between these 3 groups.