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Researchers discover the genetic cause of the most common brain malformation

An international collaboration has identified a mutation that multiplies the risk of suffering from spina bifida, which causes lifelong disability, and may also be related to schizophrenia and heart disease

Espina bífida
Liam, a boy affected by myelomeningocele and treated at Boston Children's Hospital (United States), in an image from 2019.Hospital Infantil de Boston
Nuño Domínguez

After almost a decade of work and an almost detective-like search for cases around the world, an international consortium of doctors and scientists has identified a genetic cause of the most common nervous system malformation in newborns, myelomeningocele. This condition is the most serious form of spina bifida, a set of congenital defects in the nervous system that require surgery and cause lifelong disability.

In 1980, pediatrician Richard Smithers and obstetrician Elizabeth Hibbard — who worked for years in low-income maternity hospitals where congenital malformations were common — discovered that a vitamin could dramatically reduce cases of neural tube defects. It was folic acid, a compound since then recommended for all pregnant women. Despite the historic discovery made by these two Britons, the lack of vitamin supplements or the poor adherence of mothers means that thousands of babies continue to be born with spina bifida around the world, both in developing and in rich countries. This is partly because not all cases respond to folic acid supplements.

“When a family is told that they are going to have a baby with spina bifida, the exact cause is not known,” explains Carmen Gil, president of the Spanish Federation of Spina Bifida Patients (FEBHI). Those affected suffer lifelong recurrent infections, kidney failure, lack of vision due to hydrocephalus, and irreversible cognitive sequelae. “The families say with great sadness that they have taken care with the diet and the entire pregnancy, and that despite everything, the baby has this problem. And we are talking about the most serious known malformation that is compatible with life. This study can help people to know more about this ailment and, in time, perhaps even make progress in prevention,” she adds.

It is thought that in 70% of cases, myelomeningocele is due to genetic causes and that environmental factors also likely play a role. In 2015, an international consortium was created to sequence the genome of 715 “trios” affected by myelomeningocele, the two parents and the affected child. The study collected and analyzed genetic samples from patients in the United States, Canada, Mexico, Brazil, Egypt, Nigeria, Italy, Pakistan and Georgia. In many cases, the researchers knew if the mothers had taken folic acid during pregnancy. The work identified a genetic mutation in six patients that increases the risk of malformations by a factor of 23. Some of the mothers inherited the mutation from their parents, and others developed it spontaneously during pregnancy.

In the second phase of the study, scientists analyzed another genetic database with data from more than 1,522 people who have the identified mutation, called 22q11.2 deletion. This genetic variant causes problems with the heart and other organs. The analysis of this database identified nine patients with this mutation, one of them in Madrid. The study, published on Thursday in the leading journal Science, estimates that carriers have a 15-fold increased risk of suffering from malformations in the nervous system. This genetic syndrome occurs in one in every 992 pregnancies and one in every 2,148 births, according to the research, signed by 63 authors from 10 countries.

The syndrome 22q11.2 deletion, also known as DiGeorge syndrome, affects dozens of genes. The researchers carried out a new round of experiments in mice to investigate the effect on the nervous system of deactivating the different genes involved. Their results suggest that the probable cause of the malformations is in the CRKL gene, which is involved in many communication processes between cells and is key to the healthy development of the embryo. Researchers have shown in mice that folic acid decreases the severity of congenital lesions, but does not eliminate them completely. Some mice were resistant to the supplements, which is similar to what is seen in humans.

Donna M. McDonald-McGinn, a medical geneticist at the Children’s Hospital of Philadelphia and co-author of the study, explains the significance and therapeutic potential of the findings. “This study opens an unparalleled window to understand many common birth defects, developmental differences, and psychiatric diseases, as it is the most common microdeletion syndrome,” she explains. “In addition, deletion of chromosome 22q11.2 is the most common cause of syndromic palatal anomalies and schizophrenia, and the second most common cause of congenital heart disease and developmental delay after Down syndrome. Providing insight into the etiology of less common associated features such as myelomeningocele is equally important, as once we can identify essential developmental genes such as CRKL we can begin to consider targeted therapies as well as potential environmental modifiers such as folic acid and neural tube defects,” she adds.

Encarna Guillén, president of the Spanish Association of Human Genetics and a pediatrician at the Virgen de la Arrixaca Clinical Hospital, also highlights the importance of this study. “Until now, we knew that the causes of this disease were both genetic and environmental. Being able to unravel the weight of each of these factors is a path that must be explored. In fact, the deletion identified, which is the deletion of part of chromosome 22, is one of the most frequent known. It is very interesting that they show that folic acid can counteract the effects of the deletion, which makes it even more important that future mothers follow the recommendations of taking the appropriate dose of folic acid, and it even opens the possibility of revising the criteria for including mothers with this deletion to make it even more important that they take this supplement,” she adds.

“Without a doubt, the results are interesting for basic research and suggest that the deletion of this region of chromosome 22 is somehow involved in the appearance of myelomeningocele,” says Lluis Montoliu, molecular biologist at Spain’s National Center for Biotechnology (CNB-CSIC). But the expert in rare diseases and gene editing also recalls that this new mutation does not determine whether someone will suffer from this disease. There are many people who have it and do not develop the condition and others who do not have it and still suffer from spina bifida, which once again highlights that many genetic and environmental factors have yet to be identified.

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