Do genetic tests on suspected MDS cases identify familial mutations that can cause these diseases?

FAQ Library published on November 13, 2017
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Rafael Bejar, MD, PhD
Physician-Scientist
UC San Diego Health
Moores Cancer Center
La Jolla, California

Do genetic tests on suspected MDS cases identify familial mutations that can cause these diseases?

Welcome to Managing MDS, I am Dr. Rafael Bejar. In my practice, I encounter some patients who have a family history of MDS or AML. They often ask if the genetic tests that we perform on them (in order to try to understand their prognosis better) can identify the mutations that put them at risk in the first place. The answer to this question is complex.

There are certainly families that have an increased incidence of MDS and AML that are caused by mutations that we understand. These can include genes like RUNX1 or C/EBP alpha, for example, and some of them – like GATA2 – might be associated with other syndromic features that might be notable, particularly in younger individuals. However, we are starting to learn that there are mutations in certain genes that do not necessarily manifest early in life and, in fact, can predispose to MDS much later in life. One of these genes is DDX41.

If I have a patient with a family history of MDS or AML, and I perform a gene sequencing study to try to look for mutations that might be associated with their disease, it is possible that I will identify mutations that were actually in their germline that were not acquired and are part of the reason that they have disease in the first place. The tests that we do on blood and bone marrow in these individuals are not sufficient to prove that this is a germline abnormality, and these patients should be sent for germline counseling to see if they truly carry a predisposition gene.

I will also note that there are patients who do not have any history of AML or MDS in their family who may have a mutation in their germline that is either newly acquired or newly recognized. The things to look for in this case are mutations in genes known to predispose to AML or MDS: RUNX1, C/EBP alpha, GATA2, or DDX41, for example. These mutations tend to be very abundant because they are literally in every cell that we studied in that individual. If a varying allele frequency is close to 50%, think about the possibility of a germline mutation in that individual and refer them for germline genetic counseling.

Last modified: September 27, 2017
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