Myelodysplastic Syndrome (MDS) is a group of bone marrow failure disorders where the body does not produce enough healthy, mature blood cells. A central concern for patients and their families is whether the risk is inherited. The relationship between genetics and MDS is complex; the vast majority of cases are acquired, while a small minority are linked to inherited risk factors.
Understanding Myelodysplastic Syndromes
MDS is defined by the bone marrow’s inability to properly mature blood-forming stem cells. The bone marrow becomes dysfunctional, producing abnormal cells that often die prematurely. This results in a shortage of mature, functioning blood cells in the circulation, a condition known as cytopenia.
The lack of normal blood cells affects all three major cell lines. A deficiency in red blood cells causes anemia, leading to fatigue and shortness of breath. Low numbers of white blood cells impair the immune system, resulting in frequent infections. A reduction in platelets, necessary for clotting, can cause easy bruising or unusual bleeding. In up to one-third of cases, MDS can progress to Acute Myeloid Leukemia (AML).
The Acquired Nature of Most MDS Cases
The majority of MDS diagnoses are acquired, meaning they are not passed down through families. These cases arise from somatic mutations, which are gene changes that occur spontaneously in a person’s blood stem cells during their lifetime. Since these mutations are not present at birth, they cannot be inherited. The likelihood of acquiring these mutations increases significantly with age, which is why most people diagnosed with MDS are over 65.
Several non-inherited factors increase the risk of developing somatic mutations. Exposure to intense chemotherapy or radiation therapy for a previous cancer diagnosis is a recognized cause, leading to therapy-related MDS. This secondary form often develops five to seven years after the initial treatment. Exposure to certain environmental toxins, particularly the solvent benzene, has also been linked to increased risk. Even without a clear external trigger, acquired genetic errors in genes like TET2, DNMT3A, or ASXL1 accumulate over time, eventually causing bone marrow failure.
When MDS is Familial
While most MDS cases are acquired, up to 10% are linked to an underlying inherited genetic predisposition. These familial cases are caused by germline mutations, meaning the gene change is present in every cell of the body. These inherited changes do not directly cause MDS but significantly increase the lifetime risk of developing it, often at a younger age than is typical for acquired MDS.
These inherited conditions are often referred to as myeloid malignancy predisposition syndromes. Mutations in the RUNX1 gene are a common example, associated with Familial Platelet Disorder and a high risk of progression to MDS or AML. Mutations in the GATA2 gene can lead to MDS, immune deficiencies, and other health issues, often appearing in childhood. The DDX41 gene is notable because mutations frequently present in older adults, sometimes without a clear family history, complicating diagnosis.
A doctor might suspect a familial diagnosis if there is a strong history of MDS or AML affecting multiple close relatives, or if the patient is diagnosed at a very young age. Other clues, such as unexplained low platelet counts or signs of an underlying immune disorder, can also point toward an inherited syndrome. Recognizing these patterns is important because the presence of an inherited mutation can influence treatment choices, such as selecting a healthy stem cell donor for a transplant.
Genetic Testing and Counseling
Germline genetic testing is considered for individuals who meet specific criteria, such as having a family history of blood cancers or a diagnosis of MDS before age 50. This testing analyzes non-blood cells, such as skin fibroblasts or cheek swabs, to determine if an inherited mutation is present across all cells. Identifying a germline mutation has profound implications for the patient’s medical management and the health of their family.
Genetic counselors play a specialized role by helping families understand the complex results. They explain the risk that the mutation might be passed down and advise relatives on their own risk level. For family members found to carry a predisposition gene, counselors recommend specialized surveillance or screening protocols to detect the early signs of MDS or AML. If a stem cell transplant is needed, genetic testing screens potential family donors to ensure they do not carry the predisposing mutation, which could compromise the transplant’s success.