Clinical characteristics.

DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) is characterized by an increased risk of myeloid neoplasms, lymphoid neoplasms, adult-onset single- or multiple-lineage cytopenias (including aplastic anemia), and red blood cell macrocytosis. The most common myeloid neoplasms include MDS, AML, and therapy-related myeloid neoplasms. Chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms are less common. Lymphoid neoplasms include non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.

Diagnosis/testing.

The diagnosis of DDX41-associated familial MDS/AML is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in DDX41 identified by molecular genetic testing.

Management.

Treatment: Standard neoplasm-specific therapy; allogeneic hematopoietic stem cell transplant evaluation early in the course of hematologic malignancy if appropriate based on the age of the individual, malignancy, and health status – including identification of potential related donors for genetic counseling and genotyping.

Surveillance: Complete blood count with differential every six to 12 months or more frequently as clinically indicated; annual clinical examination for constitutional signs and symptoms of MDS/AML (e.g., fatigue, infections, bleeding, and skin changes). Consider bone marrow biopsy and aspirate with cytogenetics.

Genetic counseling.

DDX41-associated familial MDS/AML is inherited in an autosomal dominant manner. To date, all reported individuals diagnosed with DDX41-associated familial MDS/AML whose parents have undergone molecular genetic testing have the disorder as the result of a pathogenic variant inherited from a parent. The heterozygous parent may or may not have developed a hematologic malignancy. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Once the DDX41 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) should be suspected in individuals with the following clinical, laboratory, or family history findings.

Clinical findings

• Myeloid neoplasms. Most common types are MDS, AML, therapy-related myeloid neoplasms, with age of onset typically in the sixth decade.
  Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms.
• Lymphoid neoplasms (less common). Types include non-Hodgkin lymphoma (follicular lymphoma most frequent), Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, with age of onset typically in adulthood.
• Aplastic anemia (rare)

Laboratory findings

• Unexplained blood count abnormalities including mild single- or multiple-lineage cytopenias and/or macrocytosis (in 40%-66%)
• In individuals with MDS/AML:
  • Bone marrow hypocellularity
  • Previous history of cytopenia
  • Personal history of hematologic malignancy (including lymphoid) or solid cancer
  • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology
  • Normal karyotype (in 59%-85%)
  • One or more DDX41 pathogenic variant(s) identified in DNA from malignant myeloid cells. NOTE: The presence of two DDX41 pathogenic variants in malignant myeloid cells, especially if one has a variant allele frequency (VAF) >0.4, is highly suggestive of the presence of this variant in the germline. The most common acquired variant (most often occurring at a lower VAF in combination with a pathogenic germline variant) is p.Arg525His. This pattern of a germline variant and a second, acquired variant in DDX41 in malignant myeloid cells occurs in 50%-88% of individuals with MDS/AML who have DDX41-associated familial MDS/AML.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) of hematologic malignancies (especially MDS/AML), unexplained cytopenias, and/or macrocytosis.

• Absence of a known family history does not preclude the diagnosis; Only 27%-39% of individuals with a germline DDX41 pathogenic variant have a family history of hematologic malignancies.
• Penetrance of hematologic malignancies appears higher in males than females (3:1) which may result in a male-predominant familial hematologic malignancy pattern.

Establishing the Diagnosis

The diagnosis of DDX41-associated familial MDS/AML is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in DDX41 identified by molecular genetic testing (see Table 1).

Note: (1) Malignant myeloid cells from individuals with a germline DDX41 pathogenic variant frequently demonstrate both the germline and a somatic DDX41 variant. (2) Identification of a heterozygous DDX41 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings may be diagnosed using gene-targeted testing (see Option 1). However, individuals with a germline DDX41 pathogenic variant can exhibit significant clinical heterogeneity. Individuals may present with hematologic malignancies or cytopenias that are indistinguishable from other inherited hematologic disorders. In such instances it may be more efficient to pursue genomic testing (see Option 2).

Note: (1) Testing for a germline pathogenic variant should not be performed on blood, bone marrow, or other tissues contaminated with peripheral blood such as saliva, buccal cells, or DNA from direct skin biopsy without culture during an active hematologic malignancy or in individuals following allogeneic stem cell transplant. Testing of an uninvolved specimen, such as DNA derived from cultured skin fibroblasts, is imperative. (2) Testing of blood or bone marrow during complete remission from a hematologic malignancy may also be performed to detect a germline variant; however, residual somatic variants, especially those associated with clonal hematopoiesis, may be detected. This testing option should therefore be reserved for rare circumstances and confirmatory testing on DNA derived from cultured skin fibroblasts is recommended for any abnormal results.

Clinical Description

DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) is characterized by an increased risk of myeloid neoplasms, lymphoid neoplasms, adult-onset single- or multiple-lineage cytopenias, male predominance, and red blood cell macrocytosis. To date, more than 200 individuals have been identified with a confirmed or presumed germline disease-causing heterozygous variant in DDX41 [Polprasert et al 2015, Cardoso et al 2016, Lewinsohn et al 2016, Li et al 2016, Berger et al 2017, Kobayashi et al 2017, Diness et al 2018, Quesada et al 2019, Sébert et al 2019, Vairo et al 2019, Maierhofer et al 2020, Polprasert et al 2020, Bannon et al 2021, Choi et al 2021, Qu et al 2021, Zhang et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been identified.

Penetrance

Penetrance may be reduced. Only 27%-39% of individuals with a myeloid malignancy and a germline DDX41 variant have a family history of hematologic malignancies [Sébert et al 2019, Bannon et al 2021]; whereas a striking, highly penetrant MDS/AML phenotype has been observed in familial series [Lewinsohn et al 2016]. Development of MDS/AML appears to occur more frequently in males than females (3:1 predominance) [Polprasert et al 2015, Quesada et al 2019, Sébert et al 2019].

Nomenclature

In the 2016 WHO classification of myeloid neoplasms and acute leukemia, DDX41-associated familial MDS/AML is designated as "myeloid neoplasms with germline DDX41 mutation" and is included in the subcategory of myeloid neoplasms with germline predisposition without a preexisting disorder or organ dysfunction [Arber et al 2016].

Prevalence

Approximately 1.5%-6.1% of individuals presenting with MDS/AML have been found to have a germline DDX41 pathogenic variant [Sébert et al 2019, Maierhofer et al 2020, Choi et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DDX41-associated familial MDS/AML, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

No evidence-based guidelines on the type of testing or frequency of surveillance for DDX41-associated familial MDS/AML have been published. The table below reflects published expert opinion-based recommendations.

Agents/Circumstances to Avoid

Avoid (if possible) stem cell transplant from related donors who have the familial DDX41 pathogenic variant, as donor cell-derived leukemia has been reported in individuals after allogeneic hematopoietic stem cell transplant using donors with pathogenic germline DDX41 variants [Berger et al 2017, Kobayashi et al 2017].

Avoid smoking, chemical exposure, and unnecessary radiation, as these may increase the risk of developing hematologic malignancy.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who would benefit from clinical monitoring. In general, molecular genetic testing for the familial DDX41 pathogenic variant is not recommended for at-risk family members younger than age 18 years. However, predictive testing of minors should be considered if there is a family history of childhood-onset malignancies (childhood onset of DDX41-associated malignancies has been reported but is very rare [Zhang et al 2021]).

Clinical monitoring (see Surveillance) of relatives who are heterozygous for a familial DDX41 pathogenic variant may enable earlier diagnosis (and treatment) of MDS/AML or other hematologic malignancies, minimizing the risks associated with delayed diagnosis and treatment (e.g., life-threatening complications of MDS/AML including severe anemia, sepsis, or hemorrhage or development of an advanced, treatment-refractory myeloid malignancy less likely to be cured). Initiation of clinical monitoring in adulthood (at least 10 years before the earliest onset hematologic malignancy or cytopenia diagnosis in the family) can be considered in heterozygous relatives; however, the age at which clinical monitoring should be initiated has not been established.

Note: There are currently no preemptive treatments available for asymptomatic individuals who have a germline DDX41 pathogenic variant.

For hematopoietic stem cell donation. Any relative considering stem cell donation should undergo molecular genetic testing to clarify their genetic status so that informed risk/benefit discussions for both recipient and donor can be incorporated into transplant donor-option decision making. Whenever possible, related donors who do not have the familial DDX41 pathogenic variant are preferred.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although hematologic malignancy onset is typically well beyond years overlapping with childbearing, if the family history suggests earlier onset, a complete blood count with differential can be performed prior to pregnancy to ensure no baseline abnormalities that would require additional hematologic evaluation. If new or worsening blood count abnormalities develop during pregnancy, urgent referral to a hematologist with expertise in this disorder is recommended.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Responsiveness to lenalidomide for DDX41-associated familial MDS/AML has been observed [Polprasert et al 2015, Negoro et al 2016, Abou Dalle et al 2020].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

DDX41-associated familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, all reported individuals diagnosed with DDX41-associated familial MDS/AML whose parents have undergone molecular genetic testing have the disorder as the result of a DDX41 pathogenic variant inherited from a parent. The heterozygous parent may or may not have developed a hematologic malignancy.
• DDX41-associated familial MDS/AML occurring as the result of a de novo DDX41 pathogenic variant has not been reported to date.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband, if available, to confirm their genetic status and to allow reliable recurrence risk counseling. Since the majority of probands will be adults at the time of diagnosis, parents may be deceased and unavailable. In this situation, testing of extended blood relatives (e.g., aunts, uncles, and first cousins) is recommended.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with DDX41-associated familial MDS/AML may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the DDX41 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The likelihood that a sib who inherits a familial DDX41 pathogenic variant will develop MDS/AML varies within and between families. Penetrance may be reduced and appears to be influenced by sex, with development of MDS/AML occurring more frequently in males than in females (see Penetrance).
• If the DDX41 pathogenic variant identified in the proband cannot be detected in parental leukocyte DNA, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the DDX41 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for DDX41-associated familial MDS/AML because of the possibility that a parent is heterozygous but does not have apparent manifestations of DDX41-associated familial MDS/AML because of reduced penetrance or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with DDX41-associated familial MDS/AML has a 50% chance of inheriting the DDX41 pathogenic variant and associated clinical manifestations including myeloid malignancy predisposition (see Clinical Description).

Note: If the reproductive partner of a proband is also heterozygous for a germline DDX41 pathogenic variant, offspring are at risk of inheriting biallelic DDX41 pathogenic variants. Sibs with biallelic DDX41 pathogenic variants and phenotypes including intellectual disability, developmental delay, and hematologic malignancy have been reported [Diness et al 2018].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the DDX41 pathogenic variant, his or her family members may be at risk of having a DDX41 pathogenic variant and associated clinical manifestations including myeloid malignancy predisposition (see Clinical Description).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment and suitability for hematopoietic stem cell donation.

Predictive testing (i.e., testing of asymptomatic at-risk family members is possible once the causative germline DDX41 pathogenic variant has been identified in a family member with MDS/AML or other hematologic malignancy.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• Because clinical monitoring of individuals with a familial DDX41 pathogenic variant is typically recommended to begin in adulthood, well after age 18, predictive genetic testing for DDX41-associated familial MDS/AML is generally not recommended for asymptomatic at-risk individuals younger than age 18 years unless the individual is being considered as a potential hematopoietic stem cell donor or there is a history of childhood-onset hematologic malignancies in the family. The timing of predictive genetic testing and initiation of clinical monitoring should be individualized based on the earliest diagnosis of MDS/AML in the family and the clinical scenario.
• For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of DDX41-associated familial MDS/AML, it is appropriate to consider testing of symptomatic individuals regardless of age. Parents should make their children's pediatricians aware of the family history of hematologic malignancies and DDX41-associated familial MDS/AML so that there is a lower threshold to perform a complete blood count with differential if any signs or symptoms of hematologic disorders were to develop.

Family planning

• The optimal time for determination of genetic risk in offspring of persons with a germline DDX41 pathogenic variant is before pregnancy. (Note: Molecular genetic DDX41 testing for the purpose of family planning is not recommended for individuals who develop MDS/AML or other hematologic malignancy in the absence of a molecular diagnosis of DDX41-associated familial MDS/AML.)
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of DDX41-associated familial MDS/AML or who are at risk of having inherited a familial DDX41 pathogenic variant.
• Partners of individuals known to be heterozygous for a germline DDX41 pathogenic variant (who are of reproductive age) may wish to consider genetic testing to determine the reproductive risk for having offspring with biallelic DDX41 pathogenic variants. While an exact syndrome has not been associated with biallelic germline DDX41 pathogenic variants, sibs with biallelic DDX41 pathogenic variants and phenotypes including intellectual disability, developmental delay, and hematologic malignancy have been reported [Diness et al 2018]. If both parents are heterozygous for a DDX41 pathogenic variant, their offspring have a 25% risk of inheriting biallelic pathogenic variants and a 50% risk of inheriting one pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once the DDX41 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

DDX41 encodes a DEAD-box helicase protein that is thought to play an important role in a number of cellular mechanisms. Such processes include mRNA splicing, recognition and suppression of cyclic nucleotides and double-stranded DNA from external pathogens or cellular sources, post-transcriptional regulation of protein translation, R-loop accumulation, and snoRNA and ribosomal RNA processing [Cheah et al 2017, Frame & North 2021, Weinreb et al 2021, Chlon et al 2021]. DDX41 has been documented to play a role in the innate immune response via the STING pathway which initiates type 1 interferon and other downstream inflammatory cytokine response pathways [Lee et al 2015, Jiang et al 2017, Weinreb et al 2021].

The DDX41 protein has four main structural regions: N-terminal domain, DEAD-box domain, helicase C domain, and C-terminal domain. Known germline pathogenic variants include frameshift variants throughout the gene, missense variants often affecting the highly conserved DEAD-box domain and helicase C domains but also occurring throughout the gene, and splicing region variants [Cheah et al 2017, Maciejewski et al 2017, Quesada et al 2019, Sébert et al 2019, Qu et al 2021].

Mechanism of disease causation. DDX41 is suggested to be a tumor-suppressor gene in which loss of function causes predisposition to hematologic neoplasms. Malignant transformation is thought to be due to the accumulation of additional somatic variants, most often in DDX41 [Polprasert et al 2015, Lewinsohn et al 2016, Cheah et al 2017, Quesada et al 2019, Sébert et al 2019, Polprasert et al 2020, Qu et al 2021].

Notable DDX41 variants. Germline pathogenic variants are usually frameshift, nonsense, or missense variants occurring throughout the gene [Maciejewski et al 2017, Quesada et al 2019, Sébert et al 2019, Qu et al 2021]. Approximately 50%-88% of individuals with a germline DDX41 variant and MDS/AML will be found to have a concomitant somatic DDX41 variant in tumor DNA. The somatic variants are often missense variants in the C-terminal helicase domain; p.Arg525His variants account for the majority.

Cancer and Benign Tumors

Sporadic hematologic neoplasms (e.g., MDS, AML) may occur as single tumors in the absence of any other findings of DDX41-associated familial MDS/AML and can harbor somatic variants in DDX41 that are not present in the germline [Polprasert et al 2015, Quesada et al 2019, Maierhofer et al 2020, Polprasert et al 2020, Qu et al 2021]. In these circumstances, predisposition to these hematopoietic neoplasms and tumors is not heritable. A variant allele fraction of less than 30% for the DDX41 pathogenic variant identified in tumor tissue is suggestive but not definitive of a somatic variant.

Author Notes

Dr Jane Churpek is hematologist/oncologist whose clinical practice and research focuses on the care of adults with low blood counts due to acquired and inherited causes, including clonal hematopoiesis, myelodysplastic syndrome, inherited bone marrow failure syndromes, and various other hereditary cancer predisposition syndromes. Web page: www.uwhealth.org/providers/jane-churpek-md

Kelcy Smith-Simmer is a certified genetic counselor who sees both adult and pediatric patients as well as their family members for germline genetic evaluation of hereditary hematology, inherited bone marrow failure, and hereditary cancer syndromes. Web page: www.uwhealth.org/providers/kelcy-smith-mmsc-cgc

Dr Churpek and Mrs Smith-Simmer are also a part of the North American & Australian RUNX1 and Inherited Hematologic Malignancies Consortium / The RUNX1 Research Program. Click here for additional information about this consortium.

The North American & Australian RUNX1 and Inherited Hematologic Malignancies Consortium / The RUNX1 Research Program
1482 E Valley Rd, Ste 137
Santa Barbara, California 93108
Phone: 805-880-4109
Email: gro.dpf-1xnur@ofni
Website: www.runx1-fpd.org/north-american-australian-rihmc-consortium

Acknowledgments

We would like to thank the individuals and families with DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia along with the numerous authors cited below and those omitted due to space limitations that have contributed and continue to contribute to the understanding of this condition. We also thank the GeneReviews Editors and Reviewers for their suggestions and contributions to the development of this GeneReview chapter.

Revision History

• 28 October 2021 (sw) Review posted live
• 3 July 2021 (jec) Original submission

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