Genetic cause of most common brain malformation discovered | The science

After nearly a decade of work and an almost detective-like search for cases around the world, an international consortium of doctors and scientists has identified the genetic cause of the most common neurodevelopmental defect in newborns, myelomeningocele. The disease is the most serious form of spina bifida, a complex of birth defects of the nervous system that require surgery and cause lifelong disability.

In 1980, pediatrician Richard Smithers and obstetrician Elizabeth Hibbard, who had worked for many years in low-income maternity hospitals where birth defects were common, discovered that the vitamin could significantly reduce the incidence of neural tube defects, the structure of the fetus that gives rise to the brain and central nervous system. . It was folic acid, a compound that has since been recommended to all pregnant women. Despite the historic discovery of these two Britons, a lack of vitamin supplements or poor maternal adherence means that thousands of children continue to be born with spina bifida around the world, especially in developing countries, but also in wealthy countries, including Spain. This is partly because not all cases respond to folic acid supplements.

“When a family is told that they will have a child with spina bifida, the exact cause is unknown,” explains Carmen Gil, president of the Spanish Federation of Spina Bifida Patients. In Spain, 31,700 people suffer from spina bifida and hydrocephalus. Among these patients, more than 50% are of working age and only 40% reach 66 years of age. Unlike other countries, Spain has no official data, so it is unknown how many children are born with these defects each year. Those affected suffer from lifelong recurrent infections, kidney failure, lack of vision due to hydrocephalus, and irreversible cognitive effects. “Families note with great sadness that they took care of the diet throughout pregnancy, and that, despite everything, the child has this problem. And we are talking about the most serious of the known malformations, compatible with life. This study could help people learn more about the disease and even that progress in prevention may be possible over time,” he adds. The main demands of this group are recognition of their right to early retirement and free receipt of the medications they need.

It is thought to be due to genetic causes in 70% of cases, and environmental factors likely also play a role. In 2015, an international consortium was created to sequence the genome of 715 triplets, patients with myelomeningocele, two parents and a sick child. The study collected and analyzed genetic samples from patients from the United States, Canada, Mexico, Brazil, Egypt, Nigeria, Italy, Pakistan and Georgia. In many cases, it was known whether mothers took folic acid during pregnancy. The work identified a genetic mutation in six patients that increases the risk of birth defects by 23 times. Some of them inherited the mutation from their parents, while others developed it spontaneously during pregnancy.

In the second phase of the study, the researchers analyzed another genetic database with data from more than 1,522 people identified as having a mutation called 22q11.2 deletion. This genetic variant causes problems with the heart and other organs. Analysis of this database identified nine patients with this mutation, one of them in Madrid. The study, published this Thursday in the journal The science, According to the world’s best scientists, carriers have a 15 times greater risk of developing defects in the development of the nervous system. This genetic syndrome occurs in one in every 992 pregnancies and one in every 2,148 births, highlights the paper, signed by 63 authors from 10 countries, including Sixto García-Minaur, a clinical geneticist at La Paz Hospital in Madrid, who recently retired.

The discovered deletion, also known as DiGeorge syndrome, affects dozens of genes. The researchers conducted a new round of experiments in mice to study the effects on the nervous system of deactivating the various genes involved. Their results suggest that the likely cause of the terrible birth defects lies in the gene KRKL, is involved in many communication processes between cells and plays an important role in the proper development of the embryo. Researchers have shown in mice that folic acid reduces the severity of congenital lesions, but does not completely eliminate them. There are cases that are resistant to this contribution, which is similar to what happens in humans.

Donna M. McDonald-McGinn, a medical geneticist at the Children’s Hospital of Philadelphia (USA) and co-author of the study, explains its relevance and therapeutic potential. “This study provides an unprecedented opportunity to understand many common birth defects, developmental differences and mental illnesses, as it is the most common microdeletion syndrome,” he explains. “In addition, deletion of chromosome 22q11.2 is the most common cause of syndromic palatal abnormalities and schizophrenia, and the second most common cause of congenital heart defects and developmental delays after Down syndrome. It is equally important to understand the etiology of less common comorbidities such as myelomeningocele, because once we can identify important developmental genes such as CRKL, we can begin to consider targeted therapies, as well as potential environmental modifiers such as folic acid and neural defects. tubes. ” he adds.

Encarna Guillen, president of the Spanish Association of Human Genetics and pediatrician at the Virgen de la Arrixaca Clinical Hospital, emphasizes the importance of this study. “Until now, we knew that the causes of this disease are both genetic and environmental in nature. Being able to unravel the significance of each of these factors is a path that needs to be explored. In fact, the deletion discovered, which is the absence of part of chromosome 22, is one of the most common known. Very interestingly, they show that folic acid can counteract the effects of the deletion, making it even more important that expectant mothers follow recommendations to take an appropriate dose of folic acid, even opening up the possibility of revising the criteria for inclusion in the program. mothers who have this deletion need to pay even more attention to taking this supplement,” he emphasizes.

Luis Montoliu, a molecular biologist at the National Center for Biotechnology (CNB-CSIC), evaluates the new research. “Without a doubt, the results are of interest for basic research and suggest that the deletion of this region of chromosome 22 is somehow associated with the appearance of myelomeningocele.” But the rare disease and gene editing expert also remembers that this new mutation does not determine whether someone will suffer from the disease. There are many people who have it but do not develop the condition, as well as others who do not have it and still suffer from spina bifida, further emphasizing that it is a disease with many genetic and environmental factors. which have yet to be identified.

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