Is CMML Inherited? Should My Family Get Genetic Testing?

For the vast majority of people, chronic myelomonocytic leukemia (CMML) is not an inherited condition, and healthy family members do not need to be routinely tested for it ^[1].

When you are diagnosed with CMML, your care team will likely run molecular genetic tests on your blood or bone marrow to help guide your prognosis and treatment. These tests usually reveal genetic mutations with names like TET2, SRSF2, ASXL1, or RAS ^[1]. It is completely natural to see the word “mutation” and worry that you might have passed this disease to your children or inherited it from your parents. However, more than 95% of patients with CMML have somatic mutations ^[1]. This means the genetic changes were acquired during your lifetime in your blood-forming cells, rather than being passed down through your family ^[1]. Finding one of these common CMML mutations in your blood is not evidence that your unaffected relatives carry an inherited risk ^[2].

The Rare Exception: Inherited Predisposition

In a small percentage of cases, CMML and related blood disorders can be linked to an inherited predisposition ^[3]. These are caused by pathogenic germline variants—genetic changes that you are born with and that are present in every cell of your body ^[3].

The most well-recognized gene associated with an inherited risk for adult myeloid neoplasms (a group of blood cancers that includes CMML) is called DDX41 ^[4]. However, it is not the only one; specialists may also look for changes in genes like RUNX1, GATA2, CEBPA, or ETV6 depending on your personal and family history ^[5][4]. Having an inherited predisposition means there is a susceptibility or higher risk for developing blood cancers, not a 100% certainty that the cancer will occur ^[6].

You and your doctor might consider the possibility of an inherited predisposition if you have any of these “red flags”:

• A personal or family history of multiple blood cancers (like myelodysplastic syndrome, acute myeloid leukemia, or CMML) ^[7].
• A lifelong history of unexplained low blood counts (cytopenias) or bone marrow failure ^[8].
• Unusually young age at diagnosis, or multiple generations in your family with blood diseases ^[8][9].
• A suspected variant found on your initial blood or bone marrow test that is known to sometimes be inherited (such as DDX41) ^[4].

Because families can be small, or relatives’ medical histories might be unknown, an inherited predisposition can occasionally be present even without a striking family history ^[8].

Why Standard Testing Isn’t Enough

If your doctor suspects an inherited condition, standard blood or bone marrow molecular tests cannot give a definitive answer. Blood and bone marrow contain malignant cells or cells with acquired somatic mutations that can mimic an inherited trait ^[10][11]. Even a cheek swab or saliva test can be contaminated by these blood cells ^[6].

To confirm a true germline variant, doctors must test tissue that is not affected by the blood cancer ^[10]. The “gold standard” for this is testing cultured skin fibroblasts, which requires a small skin punch biopsy (sometimes done at the same time as a bone marrow biopsy) ^[10][12]. These skin cells must be grown in a lab, so results can take several weeks ^[12].

It is also important to note that not every “mutation” found on a test is dangerous. Some are harmless, and some are “variants of uncertain significance” (VUS) ^[4]. A VUS should not be used to make medical decisions or to test relatives ^[4].

Should My Relatives Be Tested?

Broad genetic screening of healthy relatives for CMML is not recommended ^[6]. However, if you have red flags for a hereditary syndrome, your doctor may refer you to a genetic counselor ^[7].

A genetic counselor can explain what the results might mean for you and your family, address privacy and insurance concerns, and discuss whether testing minor children is appropriate ^[7]. If a pathogenic germline variant is confirmed in you via a skin biopsy, the counselor can then coordinate targeted cascade testing—a process where your at-risk relatives are offered genetic counseling and testing specifically for that one confirmed familial variant ^[6][13].

Important exception for stem-cell donors: If a family member (like a sibling or child) is being considered as a stem-cell donor for your bone marrow transplant, it is critical to tell the transplant team if there is any known or suspected familial mutation ^[14]. The related donor should be evaluated and tested using a non-blood sample ^[15]. If a donor carries the same pathogenic germline variant, their donated blood-forming cells could create a risk of donor-derived leukemia or other severe transplant complications for you ^[14].