Is MDS Hereditary? When Should Relatives Be Tested?

Most cases of myelodysplastic syndrome (MDS) are not hereditary. The vast majority of patients develop the disease due to genetic changes that are acquired over their lifetime, often related to aging, clonal evolution, or prior medical treatments. However, depending on the age group, the specific genes tested, and the patient population, research estimates that roughly 5% to 10% of MDS cases are linked to an inherited genetic predisposition ^{[1] [2]}.

Because of this, broad genetic testing of relatives is not a routine requirement for every MDS patient. It generally becomes a priority only if there are clear signs of an inherited condition, or if a family member is being considered as a stem cell donor ^[3].

Understanding the risk of inherited MDS requires looking at the types of genetic mutations involved, recognizing the clues of hereditary disease, and ensuring the right testing methods are used.

Acquired vs. Inherited Mutations

To understand hereditary risk, it is helpful to know the difference between the two main types of genetic mutations:

• Somatic (Acquired) Mutations: These mutations are acquired during your lifetime in the blood-forming cells and are found only in the MDS clone (the abnormal population of blood and bone marrow cells). You cannot pass somatic mutations on to your children, and you did not inherit them from your parents.
• Germline (Inherited) Mutations: These mutations are present in every cell of your body from birth. They may have been passed down from a parent, or they can occur spontaneously at conception (de novo). If you have a germline mutation, you could potentially pass it on to your children.

When doctors test your blood or bone marrow to confirm your diagnosis or understand the severity of your MDS (to risk-stratify the disease), they are mostly looking at somatic mutations. Finding a mutation in a bone marrow sample does not automatically mean it is an inherited germline mutation, even if the mutated gene is one sometimes associated with hereditary risk ^{[4] [5]}.

Clues Your MDS Might Be Inherited

While inherited MDS is uncommon, several clues might prompt your care team to suggest a hereditary evaluation. These clues often involve history that predates the MDS diagnosis:

• Younger age at diagnosis: Developing MDS as a child, young adult, or younger than the typical age for MDS, which is usually over 65 ^[4].
• Family history: Having blood relatives with MDS, acute myeloid leukemia (AML), or other early-onset cancers ^[6].
• Personal medical history: A lifelong history of unexplained low blood counts (cytopenias), severe recurrent infections, or unusual immune system problems ^[7].
• Physical or other organ problems: Certain physical features present from birth, or a history of other specific conditions like pulmonary fibrosis (scarring in the lungs) or lymphedema (swelling caused by a buildup of lymph fluid) ^{[6] [7]}.

It is important to note that the absence of a family history does not entirely rule out an inherited predisposition. For example, inherited mutations in the DDX41 gene often do not cause MDS until adulthood, and many of these patients do not have a known family history of blood cancers ^[8]. Because of this, some experts advocate for broader consideration of germline testing in MDS, regardless of the patient’s age ^[2].

Getting the Right Test: Non-Tumor Samples

Blood and bone marrow tests can raise suspicion of a hereditary condition, but they usually cannot definitively prove it. Because blood and marrow contain the abnormal MDS cells (and sometimes other age-related clonal changes), a mutation found there might just be a somatic change ^{[4] [9]}.

To definitively confirm an inherited mutation, the genetics laboratory generally needs to test a non-hematopoietic (non-blood) sample. The preferred sample—often considered the “gold standard”—is cultured skin fibroblasts, which are cells grown from a tiny skin biopsy ^{[10] [4]}. While saliva or cheek swabs are easier to collect and may be acceptable in some settings, they can sometimes be contaminated by blood cells, making a skin biopsy necessary to be certain ^{[10] [11]}. Your genetics specialist will choose the most appropriate sample for your situation.

Genetic Counseling and Testing Relatives

Before undergoing testing for an inherited predisposition, you should be referred for genetic counseling ^[4]. A genetic counselor can help you understand the risks, privacy implications, and the potential emotional impact on you and your family.

If a genetic evaluation is done, it is important to understand what the results mean for your relatives:

• Pathogenic or Likely Pathogenic Variants: If a clear, disease-causing germline mutation is confirmed, your counselor may recommend cascade testing (targeted testing of blood relatives) ^[12]. However, having the mutation does not guarantee the relative will develop MDS; the exact risk (penetrance) depends on the specific gene and inheritance pattern involved.
• Variants of Uncertain Significance (VUS): Sometimes a genetic change is found, but doctors aren’t sure if it causes disease. A VUS should not be used to test unaffected relatives or assume they are at risk ^[13].
• Somatic Mutations: Unaffected relatives do not need to be tested for acquired MDS mutations found only in your bone marrow.

Protecting Family Members as Stem Cell Donors

If you are a candidate for an allogeneic hematopoietic stem cell transplant (where healthy blood-forming stem cells from a donor replace your diseased bone marrow), testing family members becomes critically important if a hereditary condition is suspected.

When a patient has a known inherited form of MDS, the transplant team must evaluate related donors (like a sibling or adult child) very carefully. If the family member carries the same inherited mutation, using their stem cells can increase the risk of a rare complication called donor-cell leukemia, where the donor’s cells eventually develop into a new blood cancer in the recipient ^{[14] [3]}.

For this reason, potential family donors should undergo targeted genetic testing for the familial mutation before they are approved to donate ^[15]. If the related donor is found to carry the mutation, the transplant team will evaluate the safest path forward, which may include selecting a matched unrelated donor instead ^[16].