A 65-year-old man presents for evaluation of pancytopenia. Hemoglobin is 8.8 g/dL (normal range, 13.5-17.5 g/dL), absolute neutrophil count is 700 cells/µL (normal range, 1,700-7,500 cells/µL), and platelet count is 85 K/µL (normal range, 160-370 K/µL). A bone marrow biopsy and aspirate are performed showing multilineage dysplasia and 5 percent blasts consistent with a diagnosis of myelodysplastic syndrome (MDS) with excess blasts (MDS-EB-1). Karyotype is 46,XY. A myeloid malignancy–focused genetic testing panel performed on DNA from his diagnostic bone marrow specimen identifies a pathogenic RUNX1 variant (p.R201X) at a variant allele frequency of 25 percent. He is healthy without comorbid health conditions. Hematopoietic stem cell transplantation is being considered. He has one sibling and notes that she was also recently diagnosed with MDS at age 60 years. He asks if this family history is significant.
What is a “significant” family history in this context?
When a patient presents as we expect, falling within a typical age at diagnosis without any unusual features, the family history can be easy to forget. However, in this case, dueling donor searches bring the family history to the forefront. What constitutes a “significant” family history in adults with MDS or acute myeloid leukemia (AML)? The simple answer is any family with two or more cases of hematologic malignancies or unexplained cytopenias in first- and/or second-degree relatives, or with individuals with multiple cancer diagnoses, require more investigation. Approximately 10 to 12 percent of adults with myeloid malignancies will report at least one close relative with a hematologic malignancy.1,2 Thus, more than just the rare patient will require a more detailed assessment. The more cases within a family, presence of other signs or symptoms of known hereditary hematologic malignancy syndromes (HHMS), and/or presence of pathogenic variants in genes that cause known HHMS on a myeloid malignancy panel would all add to the significance.3-5 Of note, nearly all of the known HHMS are incompletely penetrant, meaning that individuals carrying a pathogenic variant within a family may remain healthy without any syndrome-related health conditions, consequently contributing to an underwhelming family history. In fact, multiple studies have found that 40 to 70 percent of individuals diagnosed with an HHMS have no significant family history.6-8
Is an HHMS a realistic possibility in a 65-year-old?
Yes, absolutely. Contrary to our expectation that hereditary syndromes are mainly relevant for the adolescent and young adult (AYA) populations, investigations in older adults are changing this paradigm. For example, germline pathogenic variants in a single gene, DDX41, which cause the syndrome familial MDS/AML with mutated DDX41, have been identified in 1 to 2.8 percent of unselected MDS/AML cases.7,9,10 The median age at onset of MDS/AML in this syndrome is 65 years.11 Similarly, MDS/AML onset occurs at a median age of 53 years in individuals with a short telomere syndrome.12 HHMS caused by pathogenic variants in multiple other genes, including GATA2, RUNX1, TP53, and even compound heterozygous FANCA, have first presented in individuals age 60 years or older. Thus, germline genetics are relevant to patients with MDS/AML presenting in this age range. We await large studies from diverse populations to accurately estimate the combined chance of finding a relevant germline variant in any gene.
What should the next step be in working this patient up for a possible HHMS?
The next step would be an expedited hereditary hematology-focused evaluation to flesh out additional history details that may immediately change the likelihood of an HHMS diagnosis and/or the expected yield of genetic testing.
Depending on each provider’s level of comfort and resources available, this could mean a dedicated visit with the original provider or referral within an institution or to a center of excellence. Where available, partnering with a genetic counselor has multiple advantages. Genetic counselors are skilled at collecting and interpreting an individual’s personal medical, exposure, and family history to provide an accurate genetic risk assessment, and in selecting and coordinating appropriate germline genetic testing within the correct timeframe. They are also invaluable for helping individuals and families navigate the complexities of genetic information, including how to use it to make informed health care decisions and how and when to extend testing to additional at-risk family members.
Real-world challenges. Expert consultation may not be available for multiple reasons. Globally, there is an extensive shortage of genetic counselors.13 Access to appropriate genetic tests can also be an issue due to insurance restrictions, cost, or lack of an appropriate test or testing laboratory.
Potential solutions. Developing collaborative partnerships between hematologists and geneticists or genetic counselors can enhance training for both parties and build an important resource for the future. Self-education and provider-to-provider consultation with experts can help. Both telephone and video conferencing have been successfully implemented to increase access to and uptake of genetic testing for hereditary breast cancer. It will be interesting to see if current expansions in telemedicine can be deployed to extend hereditary hematologic malignancy specialty consultation to regions where in-person access is limited.
Further evaluation reveals that there are other family members with hematologic malignancies (Figure). His donor search has not identified an ideal unrelated donor option. The transplant team wants to know if his son can be a haploidentical donor.
Is germline genetic testing appropriate for this patient, and if so, what are key considerations in performing a genetic test in this context?
Yes, genetic testing is recommended for this patient. His personal and family history include four first- and/or second-degree relatives with a hematologic malignancy. Additionally, the specific RUNX1 variant identified in his MDS sample would be considered a pathogenic variant causative of familial platelet disorder with propensity to myeloid malignancy if present in the germline.
Key considerations for genetic testing include:
1. Know your differential diagnosis and which genes are important for analysis. HHMS feature genetic heterogeneity, meaning pathogenic variants in different genes can present with similar features. Except in rare situations in which the clinical picture is specific to a single gene or there is a known causative variant in a family, panel-based genetic testing is required.
2. Carefully choose a genetic testing laboratory and test. Multiple commercial and academic genetic testing laboratories now offer germline genetic testing for hereditary MDS/AML and/or inherited bone marrow failure syndromes. Test options, gene lists, and even regions within a single gene that are covered vary. Choosing a laboratory that has experience with the nuances of testing for HHMS can help ensure that their tests have been optimized for this specific context and that results will be interpreted using experience and the most up-to-date knowledge.
3. Select an appropriate sample for germline analysis. Peripheral blood and other tissues contaminated with blood cells are not appropriate samples for germline genetic testing in patients with active MDS/AML. A skin biopsy followed by fibroblast culture is optimal if accessible.
4. Recognize the limitations of germline genetic testing results. A negative or inconclusive germline genetic testing result does not eliminate the possibility of an underlying HHMS. The possibility of a pathogenic variant in an untested or undiscovered gene along with the chance that our current technology cannot detect a specific variant in a tested gene still remains.
How often will a patient like this one be expected to have a positive genetic test based on the currently known genes?
At present, about 30 percent of similar patients with two or more close relatives with MDS and/or AML will have an identifiable mutation.14 Yield increases in cases with specific phenotypic features such as chronic thrombocytopenia, pulmonary fibrosis, or lymphedema as seen in GATA2 deficiency. Family history patterns predominated by multiple cases of chronic lymphocytic leukemia, non-Hodgkin lymphoma, or myeloproliferative neoplasms have a lower yield, as our knowledge of specific single genes that explain these patterns for the majority of families is lacking. Providing basic information about the likelihood that the selected test will identify the causative variant for their specific history pattern is key to managing patient and provider expectations post-testing.
How would a positive or negative test impact management?
Positive. When genetic testing identifies a causative variant or variants that are consistent with the clinical presentation at hand, the patient can then be counseled and treated based on syndrome-specific knowledge. These recommendations may include differences in expected chemotherapy toxicities, syndrome-specific transplantation regimens or outcomes, and other organ systems that need to be evaluated. For example, this can mean increased screening for nonhematologic malignancies (e.g., oral examination, colonoscopy or breast magnetic resonance imaging) or evaluation for presymptomatic comorbidities (e.g., pulmonary fibrosis). Cascade genetic testing can be offered to other at-risk relatives. Mutation status of potential familial donors can then help guide risk/benefit discussions.
Negative. This situation is often much more challenging. Re-evaluation of the strength of the personal and family history is critical. Getting objective details, such as pathology reports or death certificates, can ensure that the history is accurate. If the clinical history is consistent with a specific syndrome, a clinical diagnosis may be possible, and the patient treated accordingly. Without a causative variant identified, testing of at-risk relatives is not an option. In this scenario, familial donor selection can be especially complex and may require a multidisciplinary discussion of the known, quantifiable risks and benefits of available donor options weighed against possible serious, but not yet quantified, risks of using a familial donor who may carry the same familial mutation not yet detectable. Institution-specific guidelines may be needed until sufficient data are available to inform evidence-based practice.
Editor’s Note. For those interested in interpretation of genetic variants, please see the Diffusion article by Dr. Amy DeZern..
Dr. Zurbriggen, Ms. Smith, and Dr. Churpek indicated no relevant conflicts of interest.