https://orcid.org/0000-0002-6630-7879
TO THE EDITOR:
In the commentary by Kokame,1 the author raises concerns about the pathogenicity of p.Gln723Lys, as it is observed frequently among the East Asian population in the gnomAD database.
In our study,2 p.Gln723Lys was classified as pathogenic for 2 reasons: (1) it was identified as disease-causing in a Japanese family with confirmed hereditary thrombotic thrombocytopenic purpura (hTTP) diagnosis,3,4 and (2) it was rare in the gnomAD global database (minor allele frequency [MAF] 0.0001562) and East Asians (MAF 0.005570), with only 1 allele observed in admixed Americans (see table).
Global and ethnic-specific frequencies of the p.Gln723Lys variant in gnomAD
| Genetic ancestry group . | Allele count . | Allele number . | No. of homozygotes . | Allele frequency . |
|---|---|---|---|---|
| East Asian | 250 | 44886 | 1 | 0.005570 |
| Admixed American | 1 | 60034 | 0 | 0.00001666 |
| Remaining∗ | 1 | 62488 | 0 | 0.00001600 |
| African/African American | 0 | 75064 | 0 | 0.000 |
| Ashkenazi Jewish | 0 | 29604 | 0 | 0.000 |
| European (Finnish) | 0 | 62980 | 0 | 0.000 |
| Middle Eastern | 0 | 6062 | 0 | 0.000 |
| European (non-Finnish) | 0 | 1180022 | 0 | 0.000 |
| Amish | 0 | 912 | 0 | 0.000 |
| South Asian | 0 | 91090 | 0 | 0.000 |
| Total | 252 | 1613142 | 1 | 0.0001562 |
| Genetic ancestry group . | Allele count . | Allele number . | No. of homozygotes . | Allele frequency . |
|---|---|---|---|---|
| East Asian | 250 | 44886 | 1 | 0.005570 |
| Admixed American | 1 | 60034 | 0 | 0.00001666 |
| Remaining∗ | 1 | 62488 | 0 | 0.00001600 |
| African/African American | 0 | 75064 | 0 | 0.000 |
| Ashkenazi Jewish | 0 | 29604 | 0 | 0.000 |
| European (Finnish) | 0 | 62980 | 0 | 0.000 |
| Middle Eastern | 0 | 6062 | 0 | 0.000 |
| European (non-Finnish) | 0 | 1180022 | 0 | 0.000 |
| Amish | 0 | 912 | 0 | 0.000 |
| South Asian | 0 | 91090 | 0 | 0.000 |
| Total | 252 | 1613142 | 1 | 0.0001562 |
Population with unspecified ethnicity.
Kokame’s commentary questions whether p.Gln723Lys is truly disease-causing, noting a MAF of 0.011 in the ToMMo 54KJPN Japanese genetic database and suggesting that variants with such a frequency are unlikely to cause hTTP. Although this is likely the case, examples such as the c.3178C>T (p.Arg1060Trp) and c.4143_4144dupA (c.4143dup) variants in Norway—reaching MAFs of 0.33% to 1%—suggest that some pathogenic variants may be more common in certain ethnicities due to a founder effect.5 Although distinct from p.Gln723Lys—which has been identified in healthy individuals with normal ADAMTS13 levels and lacks functional studies, suggesting it is likely a benign or low-risk variant6—the pathogenicity of p.Arg1060Trp is more compelling. It is supported by functional studies and multiple reports confirming its role as a disease-causing variant in hTTP patients. Of note, despite the presence of p.Arg1060Trp in up to 1% of the population, no homozygous patients were found among hTTP patients in Norway.5 In gnomAD, only 1 case of homozygous p.Gln723Lys was observed among over 800 000 individuals, whereas 3 cases were homozygous for the well-documented pathogenic p.Arg1060Trp. Recombinant ADAMTS13 harboring p.Gln723Lys is key to determining its pathogenic or benign potential.
Excluding p.Gln723Lys from our analysis has a minimal impact on the global prevalence of hTTP (reducing the estimate from 23 to 22 per 106), reinforcing our conclusion that hTTP remains underdiagnosed worldwide.
Acknowledgments: This work was partially supported by the Italian Ministry of Health (Bando Ricerca Corrente). The Hemostasis & Thrombosis Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico is member of the European Reference Network (ERN) on Rare Haematological Diseases EuroBloodNet-Project ID No 101157011. ERN-EuroBloodNet is partly cofunded by the European Union within the framework of the Fourth EU Health Programme. The Department of Pathophysiology and Transplantation, University of Milan, is funded by the Italian Ministry of Education and Research: Dipartimenti di Eccellenza Program 2023 to 2027.
Contribution: O.S. wrote the manuscript; and F.P., I.M., J.N.G., and A.C. carefully revised the manuscript.
Conflict-of-interest disclosure: F.P. reports participation at educational meetings of Takeda and Spark, and the advisory board of CSL Behring, BioMarin, Roche, Sanofi, and Sobi. The remaining authors declare no competing financial interest.
Correspondence: Flora Peyvandi, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via Pace 9, 20122 Milan, Italy; email: flora.peyvandi@unimi.it.
