This is the story of Daniel and Maite. A couple with an ancestor who crossed into their family tree centuries ago and passed on an unknown 'mutated' gene. The story of a fateful lottery with a 25% chance of winning. And they won... twice. First, Tomás was born. Then, Irene. Both children suffered serious after-effects from rare intracranial hemorrhages suffered in their mother's womb. Tomás died at just six years old in 2022. Irene is now four years old and receives palliative care at Son Espases Hospital. Daniel and Maite come from different places; their families were not related and did not know each other. They had no family ties. They married and had two children, unaware that this common ancestor left them with an inheritance they could not have imagined. They both had a 'mutated copy' of a chromosome that caused these cerebral hemorrhages in the fetus during pregnancy and put the baby's life at risk at birth. A disease without a name and never before described. Related News Report No From Infanta Leonor to the Romanovs: The true story revealed by DNA Patricia Biosca From the supposed lost children of the last kings of France to the 'blood disease' in European houses, the genes of royal dynasties shed some light on shadows and myths When they had their firstborn, no one suspected the genealogical ties. Tomás was born with serious after-effects. Then came Irene, also with cerebral palsy. "Then we began to suspect that this case was due to a genetic factor," biologist and geneticist Damià Heine explains to ABC. After two years of joint research with a multidisciplinary team from the Son Espases hospital in Palma, he discovered that behind the rare intracranial hemorrhages there was a genetic mutation in both grandmothers - both paternal and maternal. Eureka. The geneticist who has served as a beacon for the Damià Heine family completed his doctoral thesis at Rutgers University in the USA and his postdoc at the Center for Biological Research (CSIC) in Madrid. He returned to Mallorca in 1999 to create the Molecular Genetics Diagnostic Laboratory at Son Dureta Hospital, now part of the Clinical Diagnostics and Molecular Genetics Unit at Son Espases University Hospital, which centralizes all public healthcare genetics in the Balearic Islands. He coordinates the "Health Genomics" research group at IDISBA (Balearic Islands Health Research Institute), which also includes Dr. Jessica Hernández, who performed the dating of the ESAM mutation and has just received funding to study ESAM using CRISPR approaches and better characterize its function, location, and pathogenicity mechanisms. To find the gene and the ancestor who passed it on, you have to go to the Genetics laboratory at Son Espases Hospital in Mallorca, where Dr. Heine sequenced the couple's genome. The Molecular Diagnostics and Clinical Genetics Unit at Son Espases Hospital analyzed all the genes of these Mallorcan siblings several times, but at first, they didn't find a shared suspected gene. "When we found a suspected variant, we saw that the other brother didn't have it," he recalls. The experts then thought the cause could be a recessive genetic disease and began searching for genes with a very specific "requirement": they had to have two mutations in the same gene. Two "bad" copies "We all have two chromosomes that we have inherited from our mother and our father. In a recessive genetic disease, you have to have both mutated genes, that is, both copies are the same. Why? "Because a single mutated copy wasn't enough to develop the disease, but if they inherited two 'bad' copies from their parents, they had two mutated copies and that explained the disease," the expert argues. And that's how they found ESAM. An unknown gene that had a very serious genetic mutation and that had never been implicated in any human disease previously. "This gene encodes the protein in blood vessels and, therefore, was a very good candidate to be the cause of this disease." Indeed, when they analyzed Maite and Daniel's genogram, they saw that each carried one good copy and one commutation. "The parents had had the bad luck, with a probability of 25% in each pregnancy, of passing on the two bad copies from their father and mother to both their son and daughter," Heine laments. Desktop Code Mobile image, amp and app Mobile Code AMP Code 3000 APP Code "We calculated and saw that the common ancestor was possibly between 750 and 1,000 years ago. "They had the bad luck of two people with a common ancestor a thousand years ago getting together. And on top of that, they passed on to each of their children the two mutated copies that caused the disease," the biologist and geneticist emphasizes. They also discovered that the mutation came from their grandmothers. A surprising finding, since one came from the peninsula and the other from Mallorca, so there was no consanguinity to explain the disease. "We didn't expect to have common ancestors, considering our very disparate ancestry," Daniel and Maite admit, still surprised. As a result of this case, Son Espases Hospital was able to describe a new disease caused by this gene, which was previously unknown to be the cause of human disease. A disease that, for now, has no name. "More than the name or the label, for us the important thing about this discovery has been knowing what kind of disease it is and understanding the possible applications in related diseases," acknowledge this couple, who agreed to this report to help publicize their case with the intention of helping other people in a similar situation. The Mallorcan is the only case registered in Europe, but Dr. Heine believes that the discovery of the ESAM gene will bring more patients to light who did not have the "label" and will allow for further research. Although the case of these siblings was resolved, the Son Espases Genetics team continued investigating. They entered the results into Genematcher, an application that functions as a kind of "Tinder" for genetics and connects researchers studying the same topic. That same day, they were contacted by an international consortium that had found other patients with this affected gene around the world, and they learned that there are four families in Turkey—with some patients already in their teens—two in Israel, and one in Algeria, in addition to the Mallorcan one. "They are people who don't have the same mutations, but they basically experience the same thing: they suffer hemorrhages in the uterus, their children have serious neurological problems when they are born, they don't walk or talk..." reveals Heine, who recently published this study in the American Journal of Human Genetics, one of the most prestigious and influential journals on human genetics. The multidisciplinary research at Son Espases Hospital has continued for the last two years. The participants included the obstetricians who detected the hemorrhages during pregnancy; the pediatricians and neuropediatricians who treated Tomás and Irene at birth; the neuroradiologists who characterized the problem of these hemorrhages; clinical and molecular geneticists, as well as the research group directed by Heine together with the Pediatric Palliative Care Unit at Son Espases. "The interesting thing about this gene is that it is similar to a stroke or cerebral hemorrhage in the uterus. Therefore, these proteins are good candidates to explain how and why some strokes occur in adults, which are a serious public health problem," she advances regarding a future line of research. Her team is already working on better characterizing this Mallorcan family to explain the causes of the disease and introduce therapies in the future. One of the unknowns that most worries experts is that cerebral hemorrhages occur in the womb and stop having them when babies are born. Controlled Medication To tell the end of this story, we must go to the present and enter the Santana-Fernández home. The girl neither speaks nor walks, but she smiles, aware of her parents' love despite everything. "Irene is doing very well, within her limitations," Maite points out, who can tell with just a glance if the little girl is having a bad day. The girl takes medication controlled by a series of specialists to treat the problems arising from brain injuries. «For the rest of the common illnesses, such as colds or fevers, she is treated in the pediatric palliative care program at Son Espases University Hospital in Palma, where Tomás was also treated until the end. "We wouldn't know what to do without this team," Maite thanks. The 25% of bad luck The parents were carriers of one good copy and one 'damaged' copy and had the bad luck, with a 25% chance in each pregnancy, of passing the two bad copies from the father and mother to both their son and daughter. Both grandmothers had the mutated gene: The mutation came from the grandmothers. One came from the peninsula and the other from Mallorca. They had no consanguinity. Two copies: They discovered a common ancestor that was between 750 and 1,000 years ago. «They had the bad luck of two people who had a common ancestor a thousand years ago getting together. And on top of that, passing on to each of their children each time the two mutated copies that caused the disease." 8 families around the world: There are 13 patients from eight families around the world. From Turkey, Israel, and Algeria. All have had intracranial hemorrhages in utero and are children born with serious neurological problems. ESAM gene: Son Espases Hospital has been able to describe a new disease caused by this gene, which was previously unknown to cause human disease. The doorbell rings. Today it's time for a visit from the palliative care unit at home. Irene smiles because she knows them. "On the other hand, she gets tense when they go to the hospital and are seen by a professional who is a stranger to her. 'They are like family to us,' Maite says, thanking the work of the four pediatricians, five nurses, the social worker, and the psychologist who make up this service that accompanies pediatric patients throughout the journey of an incurable disease and provides support during their grief. MORE INFORMATION news No Spain and Italy successfully perform the second international cross-kidney transplant with three couples involved news No These mutations cause one of the most common congenital heart defects When Tomás died in January 2022, he was by their bedside. "They never let go of our hands. It's a gift to have that support because no one teaches you how to have two children with cerebral palsy."
