The medical detectives who search for blood disorders in family trees

César Martínez’s bone marrow is “on strike.” It doesn’t work. Or not, at least, as it should, the 52-year-old man explains.

Due to an inherited genetic mutation – unknown to him until recently – his blood factory has stopped producing red and white blood cells in the correct manner for his body. This halt in the production of blood cells has caused Martínez to develop myelodysplastic syndrome: a blood cancer that will require him to receive a bone marrow transplant in the near future. But it’s not all bad news for him. He has just received “a nice surprise.”

It turns out that his eldest son is not a carrier of the genetic alteration that makes him vulnerable to this kind of blood disorder. His father and brother, on the other hand, do have a genetic predisposition… although, for now, they are healthy. Having the mutation doesn’t necessarily imply that you’ll develop these ailments – it only means that you’re at greater risk.

The Martínez family is one of more than 100 families that have already gone through meticulous examinations by medical professionals at the Hematological Genetic Counseling Unit at Barcelona’s Vall d’Hebron University Hospital. The experts who work here are like detectives, searching for diseases of the blood in their patients’ family trees. They attempt to identify hereditary genetic alterations that increase the risk of these kinds of disorders.

Genes are the instructions that explain how each cell in the body should function. An alteration or mutation in one of these structures is like “a misspelling” in that instruction manual, explains Sara Torres Esquius, a geneticist at the unit in Vall d’Hebron. “It could be that there’s a letter change, a piece missing, a page that has been torn out… it’s the altering of the instruction book that tells us how we have to function.”

A mutation in the DDX41 gene was detected in Martínez. This can cause the bone marrow not to function properly, preventing it from correctly producing red and white blood cells. “[My bone marrow] is on strike, he’s shut the door,” the patient jokes. He’s been suffering from intense fatigue for years, with no apparent explanation. The medical tests revealed that a genetic defect was taking a toll. A strange form of anemia appeared in the tests, also caused by myelodysplastic syndrome. This is an unusual form of blood tumor – it usually appears in patients who are 80 years and older, not in someone as young as Martínez. This set off many alarms.

“After all the studies, we discovered that it was hereditary. My parents were tested: my mother was negative and my father – who is 79-years-old – was positive. My brother – 20 months older than me – is also a carrier,” Martínez sighs.

There are two copies of each instruction book: one inherited from the mother and the other from the father. If there’s an alteration in either one of them, the cells can continue to function without issues, because there’s another complete and correct copy. This is how Torres Esquius explains it to her patients: “Imagine that the bone marrow is a blood factory. It takes the instruction book that has a misspelling and doesn’t understand it, but nothing happens, because it has another book to read and pull from. To exemplify this, we can look at César’s father: we know that in one of the two copies, he has this [genetic] misspelling, but his marrow – while reading the other copy – does well. What’s happening? As we get older and there are [influential] external factors – such as diet, tobacco, pollution, etc. – we can acquire mutations. And, if I lose one page of the only [complete] copy of the book, my marrow goes to look for the other one and, seeing that it’s also wrong, it goes crazy, it goes on strike and says: ‘Hey, if they don’t explain it to me well, I’ll take a pass.’ And this is when we have myelodysplastic syndrome. In the case of César, one book is damaged because he was born that way… and another has been damaged over the course of his life.”

Warning signs

The role of the Hematological Genetic Counselling Unit is to find the inherited genetic faults that may predispose someone to hematological diseases. “What we do is detect a series of mutations in the blood that predispose [a patient] to the development of hematological and other types of cancer. When we detect this in a person, we launch a series of studies of their family and we [engage in preventative measures],” explains hematologist Julia Montoro, who is the head of this specialized unit – the first of its kind in Spain. Patients usually arrive via other specialists, after a warning signal goes off. For example, according to molecular hematologist Andrés Jerez, this can happen when several cases of hematological tumors are discovered in a single family, when a cancer appears at an earlier age than usual – like in Martínez’s case – or when a suspicious combination of various symptoms appears. “[For instance], if you have an alteration in the function of your lung, in addition to a hematological cancer, this makes us suspect that you have a problem with the telomeres (the ends of the chromosomes),” Jerez notes.

While genetic counselling teams looking into solid tumors – such as breast cancer – have been around for many years and there are units in various hospitals, the knowledge that blood tumors can also be inherited is relatively new. Montoro explains that specialized services to detect them have found that hereditary hematological cancers represent around 10% of all blood tumors. A “smaller” percentage, she admits, “but with many implications.”

“Detecting mutations is important, because we’ll be able to direct the chemotherapy treatment to avoid unnecessary toxicity. Most importantly, we can better select the donor who will give the bone marrow. If we suspect that this [genetic] alteration is in the family and the donor is a relative, we must first rule out whether he or she also has the mutation, because if we don’t, we’ll be transplanting a diseased bone marrow, just like the patient’s.”

However, Montoro warns, being a carrier of a mutation that makes one predisposed to a disease doesn’t necessarily mean that one will develop the disease. In her unit, the doctors always play with two variables: penetrance – which indicates how many carriers of the variant will develop the disease – and expressivity, which deals with how much sooner or later they will do so… and how strong the disease will be when it manifests itself. Each case is different, depending on how far the investigation into a family tree can reach.

Torres Esquius is already looking at the second cousins of Elisabeth Carabante, 40. About twenty members of her family have already passed through the consultation. She entered the unit after an alert from pediatrics: Álex – Carabante’s youngest son, who is seven-years-old today – had an abnormally low platelet count. Coincidentally, his mother also used to have a low platelet count… something she says “was always an asterisk in the tests” that the doctors never gave any importance to.

Following the genetic analysis, the team at Vall d’Hebron discovered that the little boy – like his mother – carried an alteration in the ETV6 gene, which causes fewer platelets to be produced and can cause minor blood problems, bleeding, or even blood cancer. Víctor, Carabante’s eldest son doesn’t have the genetic mutation, but Montoro’s team has already detected close to a dozen members of the Carabante family with the same anomaly. “Their case is a very clear example of penetrance and expressivity: the majority [of the family] has the alteration in ETV6 and has an alteration in platelet numbers… but [these anomalies] are not causing cancer. The penetrance rate is relatively high, but the expressivity is very variable,” the geneticist summarizes.

Early diagnoses

Elisabeth tears up while praising the work of the professionals in the unit, especially how they gave names to all the issues that were afflicting her and her family members. Martínez also applauds the answers they have given him and the relief of seeing his son free of an unwanted inheritance. Torres Esquius assures EL PAÍS that the inspection of the family trees of both families is ongoing – there’s no limit. The farther they can go, the better.

While early detection of these alterations cannot prevent future ailments, Jerez emphasizes that it does help patients address health problems early on. “There’s no preventive intervention, but it can be foreseen, in the sense that you don’t get caught in the moment of the fully flared-up disease, when the [damage] to the organs has already irritated you.”

Montoro explains that the Hematological Genetic Counseling Unit is focused on a paradigmatic case: four siblings who have a genetic alteration in common. “The first brother passed away in the United States 20 years ago: he developed pulmonary fibrosis (a lung disease) and died. The second sister – a young woman – developed pulmonary fibrosis and, in the context of a two-lung transplant, developed anemia and was eventually diagnosed with myelodysplastic syndrome. She recently died. And then the alarm went off: we called the two remaining siblings and it turns out that one was already in a clinical trial at the Hospital de Bellvitge (southwest of Barcelona) because he had mild pulmonary fibrosis, but there was nothing in his blood. The [surviving] sister doesn’t have pulmonary fibrosis, but we did a bone marrow study and we observed that she has myelodysplasia… it now seems that she’s developing pulmonary fibrosis,” the hematologist says.

All the siblings had alterations in the biology of the telomeres, due to a mutation in the TERT gene, which is responsible for the maintenance of these chromosome structures. “This is associated with the instability of the entire genome: if you lose telomeres, your [healing process is weakened] and you have more alterations and mutations,” Jerez explains. The siblings who are still alive are now under the strict surveillance of pulmonologists and hematologists, while the unit continues to search for their relatives, who may be afflicted by the same disorder.

However, not everyone wants to know. There are families that refuse to know if they are carriers of any genetic alterations that may make them vulnerable to certain diseases. Both doctors and patients agree that this is understandable. But Torres Esquius prays that, whatever decision these individuals make, they at least be informed: “The important thing is to know the information, because if you don’t know what it could imply, you can imagine that it’s something terrible, or that [it’s not anything at all]. It’s important that, after knowing the information, they decide if they want to be studied and enter an early detection program, or not.”

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