Familial/inherited MDS: rare but important to keep in mind

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Is MDS likely to be passed down from parent to child?

Written by Prof Jude Fitzgibbon, Prof Tom Vulliamy and Prof Inderjeet Dokal, Queen Mary University of London

When a patient is first diagnosed with myelodysplastic syndrome (MDS), one of the most frequent questions posed is whether the disease is likely to be passed down from parent to child, and if other family members could conceivably develop this malignancy too.

Conventionally, heritable (i.e. passed from parent to child) forms of MDS are thought to be rare and are typically, NOT considered to run in families.

Our research group at Queen Mary University of London (QMUL), with funding from the charity Bloodwise, have been collecting and storing blood and bone marrow samples from these rare patients and their families in order to better understand the nature of the faulty genes responsible for inherited MDS. This research is important for the individual families, as it provides valuable
information for treatment of the disease, assessing risk and genetic counselling, but it also offers a unique opportunity to identify the critical early genetic events that give rise or predispose patients to MDS.

Jude Fitzgibbon talks with Sophie Wintrich about familial MDS. Watch the video

Since 2016, inherited forms of myeloid malignancies, including MDS, have been included as a separate disease entity in the World Health Organisation (WHO) classification of haematological cancers.

This is leading to a greater awareness on behalf of haematologists regarding the existence of these forms of disease, enabling more tailored management of this group of at-risk individuals.

This is important, as patients with ‘familial MDS’ (i.e. with a predisposing mutation present in every cell) tend to develop symptoms at a much younger age compared to people with ‘sporadic disease’ (i.e. mutations are restricted to the MDS only).

We also appreciate that MDS can arise as part of a wider syndrome, with many patients/families initially exhibiting bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, and Shwachman–Diamond syndrome which often subsequently lead to MDS.

Why is it important to identify patients with familial MDS?

Our research is demonstrating that there isn’t a singly mutated gene responsible for familial MDS but many different genes,
some of which are also mutated in sporadic forms of the disease (RUNX1, GATA2). In comparison other mutations (in the germline) appear enriched or exclusive to inherited forms of MDS (DDX41, SAMD9) and this is offering researchers novel insights into the causes of MDS and the prospect of developing better treatments for all MDS patients.

It is, therefore, important that, when a new patient is diagnosed with MDS in the clinic, steps are taken to determine whether the disease has a significant genetic-inherited component. This is crucial, as in some subtypes of inherited/familial MDS subsequent therapy must be modified.

  • For example, if a patient has MDS associated with an underlying telomerase mutation then the chemotherapy conditioning regimen performed prior to a bone marrow transplant has to be reduced.
  • Equally, a haematologist would want to ensure that, in selecting bone marrow/stem cell donors, an asymptomatic family member with the same genetic defect is not used as the donor as the recipient could go on to develop MDS again at a later time point./li>

Germline vs Somatic (Sporadic) Mutation

Which services does the research group provide?

In order to facilitate identification and genetic categorization of inherited/familial MDS our research group (in collaboration with the Genetics Laboratory at Birmingham and support from Bloodwise) provides genetic testing in such cases. This means if a clinician suspects that their patient may have a significant genetic component they can send blood samples directly to our laboratory.

Indeed, in the future, our expectation is that every MDS patient will have a molecular profile performed as part of their overall management, to identify the specific mutations that are exclusive to their MDS and to assess if there is a significant inherited component, linked to their disease, where a mutation is present in all cells in the patient’s body.

We are also able to provide specific advice on the management of patients if a genetic defect is found in one of the many genes that are associated with inherited/familial MDS by contacting us directly (email i.dokal@qmul.ac.uk).

Furthermore, if a genetic defect is not found in one of the known familial MDS genes and there is a strong clinical suspicion for familial MDS (for example, if there is a history of multiple MDS cases in the family) then these samples are put forward for research studies aimed at new gene discovery.

In summary:

  • Familial/inherited MDS is a very heterogeneous and complicated disorder. It is thought to be rare but the precise figures on its incidence and prevalence are not known.
  • Over the last 20 years many genes have been identified that are responsible for familial/inherited predisposition to MDS and they have highlighted the importance of making specific modifications to therapy to achieve optimal outcomes.
  • Our ongoing research programme at QMUL provides genetic testing for all of these genes as well as a strong focus on identifying new disease genes where current genetic tests fail to identify a defect in at-risk families.

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