The clinical and genomic landscape of patients with DDX41 variants identified during diagnostic sequencing
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
Deleterious germ line variants in DDX41 are a common cause of genetic predisposition to hematologic malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next-generation sequencing was performed in a large cohort of sequentially recruited patients with myeloid malignancy, covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematologic malignancies to investigate the spectrum of cancer predisposition. Altogether, 5737 patients with myeloid malignancies were studied, with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germ line variants in patients with MDS and AML, and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germ line variant classification at a very strong level (as per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines). Using this approach, the MDS cohort contained 108 of 2865 (3.8%) patients with germ line likely pathogenic/pathogenic (LP/P) variants, and the AML cohort 106 of 2157 (4.9%). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared with those in patients with myeloproliferative neoplasms, B-cell neoplasm, and T- or B-cell acute lymphoblastic leukemia. In summary, we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multiexon deletions) to fully detect the landscape of possible clinically relevant DDX41 variants.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
Blood advances - 7(2023), 23 vom: 12. Dez., Seite 7346-7357 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Maierhofer, Anna [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
DDX41 protein, human |
|---|
| Anmerkungen: |
Date Completed 05.12.2023 Date Revised 10.01.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1182/bloodadvances.2023011389 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363671846 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363671846 | ||
| 003 | DE-627 | ||
| 005 | 20240114233803.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/bloodadvances.2023011389 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1256.xml |
| 035 | |a (DE-627)NLM363671846 | ||
| 035 | |a (NLM)37874914 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Maierhofer, Anna |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The clinical and genomic landscape of patients with DDX41 variants identified during diagnostic sequencing |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.12.2023 | ||
| 500 | |a Date Revised 10.01.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
| 520 | |a Deleterious germ line variants in DDX41 are a common cause of genetic predisposition to hematologic malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next-generation sequencing was performed in a large cohort of sequentially recruited patients with myeloid malignancy, covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematologic malignancies to investigate the spectrum of cancer predisposition. Altogether, 5737 patients with myeloid malignancies were studied, with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germ line variants in patients with MDS and AML, and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germ line variant classification at a very strong level (as per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines). Using this approach, the MDS cohort contained 108 of 2865 (3.8%) patients with germ line likely pathogenic/pathogenic (LP/P) variants, and the AML cohort 106 of 2157 (4.9%). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared with those in patients with myeloproliferative neoplasms, B-cell neoplasm, and T- or B-cell acute lymphoblastic leukemia. In summary, we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multiexon deletions) to fully detect the landscape of possible clinically relevant DDX41 variants | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a DEAD-box RNA Helicases |2 NLM | |
| 650 | 7 | |a EC 3.6.4.13 |2 NLM | |
| 650 | 7 | |a DDX41 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.1.- |2 NLM | |
| 700 | 1 | |a Mehta, Nikita |e verfasserin |4 aut | |
| 700 | 1 | |a Chisholm, Ryan A |e verfasserin |4 aut | |
| 700 | 1 | |a Hutter, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Baer, Constance |e verfasserin |4 aut | |
| 700 | 1 | |a Nadarajah, Niroshan |e verfasserin |4 aut | |
| 700 | 1 | |a Pohlkamp, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Ella R |e verfasserin |4 aut | |
| 700 | 1 | |a James, Paul A |e verfasserin |4 aut | |
| 700 | 1 | |a Kern, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Haferlach, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Meggendorfer, Manja |e verfasserin |4 aut | |
| 700 | 1 | |a Haferlach, Torsten |e verfasserin |4 aut | |
| 700 | 1 | |a Blombery, Piers |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood advances |d 2016 |g 7(2023), 23 vom: 12. Dez., Seite 7346-7357 |w (DE-627)NLM268683263 |x 2473-9537 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2023 |g number:23 |g day:12 |g month:12 |g pages:7346-7357 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/bloodadvances.2023011389 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2023 |e 23 |b 12 |c 12 |h 7346-7357 | ||