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Ethnic features of DDX41 mutations in ICUS/MDS/AML
HLA-matched sibling or unrelated donor was available, and his two adult offspring had the same DDX41 muta- tion (p.E7*). Fortunately, the patient’s HLA-haploidentical brother did not carry the DDX41 mutation, and the patient could undergo haploidentical hematopoietic stem cell transplantation from him. Considering that the risk of malignancy in DDX41 carriers is yet to be determined, we calculated the odds ratios of major germline DDX41 variants detected in our study (Online Supplementary Table S4). Nevertheless, an extensive population-based study is needed to obtain more reliable data that may be useful in establishing genetic counseling guidelines for germline DDX41 variants, which are cur- rently available only for donor selection in allogeneic hematopoietic stem cell transplantation.
NGS-based targeted genotyping for somatic mutations can identify patients who are at risk of hereditary hematopoietic malignancies. In a recent study, of 25 pathogenic or likely pathogenic variants with variant allele frequency >40% in 24 patients with germline tis- sues available, six variants (24%) were of germline origin – three DDX41 variants, two GATA2 variants, and one TP53 variant; DDX41 had a 100% diagnostic yield for pathogenic germline variants in that study.33 In another study, targeted NGS showed that 17 patients had puta- tive germline DDX41 variants with a variant allele fre- quency >40%, all of which were of germline origin.11 We were also able to confirm germline origin in all of the 11 patients with probable germline DDX41 mutations. In cases in which germline samples are not available, NGS- based leukemia panels seem to predict germline DDX41 variants with high probability. However, it is worth mentioning that NGS-based panels may fail to detect deletions or gene rearrangements that are responsible for the predisposition syndrome.
Our study has some limitations. The number of patients included in the study was relatively small, and this might have had an impact on the analysis for clinical associations of DDX41 mutations with clinical outcomes. Family his- tory was not systematically collected in this study, although such information is helpful in pinpointing the pathogenicity of sequence variants. We did not perform functional studies to demonstrate that sequence variants detected in this study had a deleterious effect in vivo. Experimental data can be useful to support pathogenicity, particularly for missense variants of uncertain significance. We acknowledge that these limitations may hamper the precise variant classification based on the ACMG guide- line. However, the concurrence of germline and somatic DDX41 mutations was a recurrent finding across recent
studies.5,6,10,11 This also has provided another illustration that germline alterations predispose to the acquisition of somatic mutations in the same genes which act as a sec- ond hit being associated with cancer development as demonstrated by JAK2, CEBPA, and RUNX1 muta- tions.34,35 Therefore, in cases harboring a germline DDX41 mutation, the acquisition of a somatic DDX41 mutation should be considered as strong evidence for causality. Lastly, our data may not reflect the whole Korean popula- tion, although study patients included in this study come from all across the Korean peninsula.
In conclusion, our results delineate the unique ethnic features of DDX41 mutations in Korean patients, such as higher incidence and different patterns, compared with patients from Western countries or other Asian countries. Specifically, the most common germline mutation in our cohort was p.V152G, which was not found in previous studies in other ethnicities. Our results suggest that ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 muta- tions may be predicted with a high probability by using clinical NGS-based leukemia panels based on variant allele frequency levels and public databases. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.
Disclosures
No conflicts of interest to disclose.
Contributions
E-JC and Y-UC analyzed and interpreted the data; E-JC, Y- UC and J-HL contributed to the manuscript; E-HH performed experiments. All authors provided patients’ data, reviewed, and approved the final manuscript.
Acknowledgments
We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript.
Funding
This research was supported by a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2017R1E1A1A01074383). The biospecimens and data used in this study were provided by Asan Bio-Resource Center, Korea Biobank Network (2018-08).
Data-sharing statement
For original data, please contact imeunjeee@gmail.com.
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