The 101 Marfan Genomes Project as seen by Dessie Lividikou and Laurens Ivens
Our history
Our son Sam was born on September 24, 2017. He has neonatal Marfan syndrome, a severe variant of Marfan syndrome. Marfan syndrome is a progressive disorder in which the body’s connective tissue is not produced correctly. This mainly affects the heart, lungs, skeleton and eyes. There is currently no causal treatment for Marfan syndrome. Infants with neonatal Marfan syndrome have a low life expectancy. Doctors gave Sam a maximum life expectancy of 2 years at birth.
Marfan syndrome is a genetic disorder affecting around one in 5,000 people. In three out of four cases, Marfan syndrome has been genetically transmitted within the family. In one in four people, it results from a spontaneous new mutation. Neonatal Marfan is always ” de novo “, as in Sam’s case.
Marfan syndrome is caused by a mutation in the FBN1 gene (Marfan gene), which means that fibrillin-1 protein, and therefore connective tissue, is not produced in sufficient or adequate quantities in the body.
We’ve started a blog Lieve Sam ” and through our blog, we came into contact with the parents of Aurelien, a little Belgian boy aged 2 and a half suffering from neonatal Marfan syndrome.
His parents, Romain Alderweireldt and Ludivine Verboogen, have launched a major innovative research project on rare diseases in Belgium via their ” 101 Genomes Foundation “.
The aim of the Foundation’s pilot project, the ” Project 101 Marfan Genomes “, is to create a genetic and clinical database from 101 patients with Marfan syndrome. Thanks to this database, scientists from a wide range of specialties will be able to carry out new research into this rare connective tissue disorder.
Why this search ?
Until now, it was thought that neonatal Marfan was a disease with a predictable course, caused by this ” Marfan gene ” and that all children with neonatal Marfan died within two years.
In recent years, scientists have found that there is more variation between patients in the course and severity of this disease than was originally thought. Some of this variation can be explained by earlier diagnosis and better symptomatic treatment, but it also points to natural variations. Neonatal Marfan syndrome is currently considered the most severe form of Marfan syndrome.
Similarly, in classic Marfan syndrome, there appears to be a great deal of variation between patients, and even within the same family (in which all patients carry the same FBN1 genetic mutation), there can be great differences. Some people with Marfan syndrome have few symptoms and live to a ripe old age, while others die very young.
This platform would enable scientists to study this variability in greater depth, in order to understand whether and what other genetic factors, in addition to the Marfan gene, lead to it.
Study concept
The aim of this research is to develop a database of 101 Marfan syndrome patients and to conduct research on all their genetic material[1]. Whereas until now, only the Marfan gene has been studied, the aim of this project is precisely to map all the genes[2] in these patients.
By linking all the patients’ genetic information to their syndrome and comparing it with each other, scientists can determine whether there are other genes, in addition to the Marfan gene, that influence the development of the syndrome. And if there are other genes that also have an effect on the course of the syndrome, which could possibly explain why this disease manifests itself very mildly in some patients and very seriously in others.
Mapping not just the Marfan gene, but all the genes of Marfan patients, makes this research innovative and an important addition to existing knowledge of Marfan syndrome[3].
If, when comparing Marfan patients, recurrences and similarities are found that show that other hitherto unknown genes affect Marfan syndrome, it may be possible to intervene and develop strategies that can enhance the effect of genes with a positive influence or mitigate the effect of genes with a negative influence. On this basis, other treatments or drugs can be developed in the future, which can improve patients’ health.
For setting up their 101 Genomes Foundation, Aurélien’s parents won RaDiOrg’s 2018 Edelweiss Award[4 ] for their contribution to rare diseases in Belgium.
Why hasn’t this research been carried out before ?
Since Marfan syndrome is a rare disease, and neonatal Marfan is even rarer, little is known about the wide variability in patient outcomes. Recent research shows that there is also great variability between children with neonatal Marfan. This new perspective makes innovative research possible and relevant.
What’s more, the technique needed to ” read ” a patient’s entire gene palette (the whole genome) and compare it with other patients was still inaccessible until recently.
Today, thanks to the latest scientific developments, it is perfectly possible to carry out this research at an affordable price.
What do we need ?
Two things are needed to carry out this research. Firstly, a cohort of at least 101 patients with Marfan syndrome, with a number of different FBN1 mutations and clear variability in disease severity. This will enable a genetic comparison between patients with mild and severe Marfan syndromes.
Secondly, an amount of 500,000,- euros is needed for 2018 to be able to set up and carry out the research. Part of this amount has already been collected.
This project is being carried out by the 101 Genomes Foundation, created by Aurélien’s parents, in collaboration with the King Baudouin Foundation of Belgium. A large number of national and international scientists and organizations working in the Marfan field have already pledged their support and cooperation to this project.
Laurens Ivens and Dessie Lividikou
Amsterdam April 2018
Our blog Lieve Sam www.lievesam.weebly.com
Further information on the 101 Marfan Genomes project can be found at https://f101g.org/
Professor Bart Loeys, University of Antwerp :” It’s very inspiring to see how involved Sam and Aurélien’s parents are in scientific research for a better treatment of Marfan syndrome. Their inexhaustible energy and unbridled commitment encourage us to look even harder for the missing pieces of the puzzle. The ” natural ” variability in the severity of clinical signs in Marfan patients with the same genetic mutation on the FBN1 gene tells us that nature itself finds ways to compensate at least in part for the effect of the genetic mutation. If we can discover how ” mother nature ” achieves this, we can try to find treatment methods that produce the same effect. Genetics has undergone a veritable technological revolution in recent years, and the time has come to use this technology to discover genetic explanations for clinical variations between Marfan patients. I’m happy and proud to be able to contribute to this national and international cooperation between scientists, patients and their parents. ” Professor Julie De Backer, Ghent University :” The chances of actually collaborating with patients and families in research are generally low – usually not beyond the inclusion of patients in study protocols. The opportunity offered by Romain and Ludivine is unique, allowing us to develop very concrete questions from the patient’s point of view. What they’ve learned about the syndrome in such a short space of time is unheard of, and they’ve built a solid project around it. The question of why we are so drawn to research is often asked – although the answer to this question is obvious: disorders such as Marfan syndrome are often accompanied by serious (sometimes life-threatening) problems – this is very difficult for patients and their families to bear in the first place, and even as a doctor, it doesn’t leave anyone indifferent. By taking an active part in research, we are trying (in small steps) to alleviate this suffering, and this gives us the energy we need to continue our work.. “ |
[1] The aim is to link all the genomic data from these patients to their phenotypic characteristics.
[2] Not only the specific Marfan gene, but also the entire genome of these patients.
[3] This approach is inspired by the Genome-Wide Association Study (GWAS).
[4] Rare Disease Organisation
