My wife and I were delighted to accept Véronique Vrinds’ invitation to prepare a special issue of the journal Le Cœur & la Main devoted to the ” Projet 101 Génomes Marfan ” (hereinafter P101GM) of the ” Fondation 101 Génomes ” (hereinafter F101G).

The P101GM is the result of the work of ABSM, and would certainly not exist in its present form without the support of Léon, Rémi, Yvonne, Lauriane and Véronique.

The crucial role of patient associations

Like many parents of children with rare diseases, we wanted to do something about our son’s diagnosis. We first turned to the ABSM, which welcomed us with open arms and gave us the opportunity to discover the Belgian and then the European Marfan community through VASCERN.

In this context, we gradually became interested in research into Marfan syndrome. We have found that, in addition to supporting patients and their families, patient associations play an essential role in advancing research. A communication and funding role, such as that played by the American Marfan Organization(www.marfan.org), but also a role of direct support for research, such as that assumed by the French Marfan Syndrome Association(www.assomarfans.fr).

We were particularly impressed by the French Association’s contribution to the creation of the UMD-FBN1 database. UMD-FBN1 is an open-access database launched in 2003 that allows researchers from all over the world to consult online (at www.umd.be/FBN1/) an inventory of 3044 pathogenic mutations in the FBN1 gene coding for the Fibrillin 1 protein on chromosome 15, identified as the cause of Marfan syndrome.

This unique database feeds the work of hundreds of scientists around the world, and is regularly cited in the scientific literature on Marfan syndrome. This is a very important tool that has been accompanying research for many years.

Beyond the sometimes conventional speeches, UMD-FBN1 appeared to us as concrete proof of the crucial role played by patient associations in scientific advances.

Continuing our research with the invaluable help of Dr Guillaume Smits, we then realized the limitations of UMD-FBN1 and quickly identified a gap – or a void as Cécile Chabot calls it – that the scientific community wanted to fill as quickly as possible : access to the genome.

The genomics revolution

As a result, Marfan syndrome specialists are calling for access to a version that is in some way “the best of the best”. upgraded “The UMD-FBN1 database would not only contain information on the pathogenic mutations observed on the single FBN1 gene on chromosome 15, but would also include information on all genes on all 23 chromosome pairs that make up the genome of Marfan syndrome patients.

This means that, for each patient, the database would go from a ” letter “[1 ] mutated pathogen to… 3 billion letters representing the DNA of an entire genome !

If this increase of 3,000,000,000,000 % of the volume of information available on the database was unthinkable until 2014, it is no longer the case today, since technological and bioinformatics advances now make it possible to obtain genomic information for a sequencing cost of around 1,000 euros and a data volume of the order of 300 gigabytes.

To borrow from the metaphor of galaxy observation used by the Doctor Guillaume Smits in the interview belowWith the technological and bioinformatics developments of recent years, scientists have moved from Galileo’s telescope to the Hubble telescope. ! And that’s what made the transition from genetic – individual gene study – to genomics – the study of all genes and their interactions.

Professor Paul Coucke describes this development as ” technological revolution “.

And it is the benefits of this ” genomic revolution ” that we want to make available to scientists studying Marfan syndrome, to help them better understand the disease. The ambition is that therapists will then be able to ” better inform and treat ” patients, as Professor Julie De Backer explains.

Taming the genome

The mention of the genome feeds many fantasies, which are compounded by those relating to the algorithms required to process the extraordinary volume of data that the genome represents.

While some fears are perfectly legitimate, it’s important to separate prejudice from fact. And the P101GM is part of this attempt to ” tame ” the genome.

As Dr Michel Verboogen points out, a number of such initiatives are flourishing around the world. They can be found in Iceland, Finland, France, Estonia, Canada, China, the USA, Dubai and the UK. One of the most ambitious initiatives is the ” 100,000 Genomes Project ” in the UK, which mobilizes state budgets for the benefit of numerous rare diseases – including Marfan syndrome – to use the genome for diagnostic and research purposes[2].

While the British project served as a source of inspiration for the creation of the 101 Genomes Foundation, the latter differs in that, at present, its action is focused solely on research into Marfan syndrome (P101GM), and relies exclusively on private funding.

In Belgium, on the institutional side, the Federal Center for Healthcare Expertise (KCE) published a report in early 2018 advocating the establishment of a pilot project to better understand the technology, its costs and implications before following the example of nations making progress in genome study[3]. At this stage, we understand that the KCE is suggesting that an intermediate technology[4] be retained and that resources be freed up as a priority for oncology in the care phase[5 ] and to participate in the diagnosis of rare diseases in general. The aspect of participation in the advancement of research is, according to our current understanding, not yet fully taken into account at this stage.

Nevertheless, thinking about the genome is intense in Belgium, and the Minister of Health has commissioned the King Baudouin Foundation to survey public opinion on the genome. It was against this backdrop that the King Baudouin Foundation welcomed our initiative, as Patricia Lanssiers and Gerrit Rauws explain.

Drawing on its knowledge of the genome in Belgium, the King Baudouin Foundation suggested that we structure our action in such a way that it could be replicated for other rare diseases. This is what we have done by creating the pairing of Fonds 101 Génomes and Fondation 101 Génomes, which will enable us to set up genomic projects for other rare diseases, building on the experience acquired with P101GM, as Professor Anne De Paepe explains.

All concerned

Also as part of the mission entrusted to it by the Minister for Health, the King Baudouin Foundation recently published a very interesting brochure entitled ” My DNA, all concerned ? “[6].

As its title suggests, this brochure addresses the question of individual responsibility for the genome, and the citizenship of humanity that this implies. This question, also raised by Maître Bruno Fonteyn, is particularly interesting.

Indeed, each individual whose genome is sequenced contributes to a better understanding of the human genome and how its component genes interact with each other.

This raises questions about each individual’s responsibility to contribute to a better understanding of humanity, in order to treat oneself and possibly others as well.

One example is the story of Stephen Lyon Crohn who, as a carrier of a mutation in the CCR5 gene, was genetically immune to most forms of the AIDS virus[7]. The chance discovery of this mutation and its effects has led to the development of new drugs[8].

Today, the genomics revolution is multiplying the possibilities of discovering “new” genes. superhero genes ” and extend it to the field of rare diseases, as explained by Peter O’Donnell and Alisa Herero. In other words, to discover modifier genes whose action counteracts (or a contrario amplifies) the pathogenic effect of a mutated gene at the origin of a genetic disease[9].

In this context, taking part in the genome adventure is a bit like donating blood: it can save someone else’s life, and in turn save our own.

Genomic data / phenotypic data

An essential point remains : consulting the 3 billion bases (letters) that make up the genomic data is practically useless from the point of view we are interested in.
[10]
.

To be truly useful, and to enable matches to be established scientifically, genomic data must be paired with data that describe as precisely, objectively and completely as possible the observable biological traits of the person whose genome is collected : this is phenotypic data.

In concrete terms, in the case of P101GM, it is only by having the ” genomic data / phenotypic data ” pair that researchers will be able to attempt to discover what precisely corresponds to each gene and/or mutation and their interactions. They will then be able to hope to understand the great variability in the spectrum of disorders associated with Marfan syndrome – even with an identical mutation – which, as researcher Aline Verstraeten has observed, cannot be explained at present.

This knowledge will enable us to better monitor and treat patients, as Professor Catherine Boileau explains, and to respond to the concerns of patients’ families, as expressed by ABSM President Véronique Vrinds.

Securing and anonymizing personal data

The 3 billion letters that make up genomic data are unintelligible to any human being without a suitable interface. What’s more, this data is virtually identical – to almost 99 % – for all individuals belonging to the human race. For the most part, therefore, it is difficult to consider this data shared by all as personal data in the strict sense. On the other hand, there’s no doubt that the balance, drowned in a sea of letters, is so unique to each and every human being. Access to this balance – and to the whole from which it can be isolated – must therefore be anonymous and secure.

Phenotypic data are also tricky to process, since they are personal data which in fact correspond to an individual’s complete medical file. These phenotypic data must therefore be treated with the same care as a person’s medical file, which would be made available to researchers.

At the same time, the link with genomic data must be protected.

We have surrounded ourselves with a team of lawyers specialized in personal data protection issues, to put in place a legal framework that guarantees the secure processing of patient data in full compliance with current legislation. You will read below the interventions of several members of our team such as : Michael Lognoul, Assistant at the University of Namur (CRIDS) ; Bruno Fonteyn, Lawyer at the Brussels Bar specializing in life sciences issues and ; Cécile Chabot, lawyer in charge of the transposition of the “General Data Protection Regulation” (GDPR) in companies.

What we do and what we don’t do

To understand the issue of secure access to the / phenotypic cross-referenced genomic database that the P101GM aims to set up, it’s essential to first understand what we’re doing and what we’re not doing.

As part of P101GM, the 101 Genomes Foundation has set itself the task of funding :

• Complete genome sequencing of 101 patients genetically diagnosed with Marfan syndrome using the gold standard on the market (currently Illumina’s 60-cover technology (WGS 60x)) ;
• Storage of this information in three formats (FastQ, BAM and VCF) for 10 years ;
• Setting up a bioinformatics platform to cross-reference genomic data with the corresponding phenotypic data ;
• The integration of phenotypic data from 101 patients on the  platform;
• Managing access to the platform and any links with other platforms.

In the same spirit as UMD-FBN1, the Foundation does not fund the work of any particular research team, but makes available to all research teams worldwide a resource that enables them to substantially reduce their research costs and more rapidly carry out their own investigations into Marfan syndrome.

To put it simply, scientific research will be carried out downstream of the bioinformatics platform set up as part of P101GM. And it’s already a ”  ! ” to research, as explained by Lauriane Janssens, researcher and President of the European Marfan Network.

Access

The different levels of access will be managed by a specific Access Committee.

Based on the GnomAD model, it will be possible to carry out an open-access search on genomic data in raw format, with no link to phenotypic data.

Access to the cross-referenced data will be made available to all research centers studying Marfan syndrome, on reasoned request.

Any requests to recontact cohort members will go through the Access Committee.

To encourage the pharmaceutical industry to invest in the development of new drugs for people with Marfan syndrome, a form of secure licensed access will also be set up to help fund the tool’s development.

Parallel searches

Investigations linked to the implementation of P101GM have already brought to light some interesting elements on which Dr Guillaume Smits’ team at theInteruniversity Institute of Bioinformatics in Brussels ((IB)²) is working, and which we look forward to seeing come to fruition.

Questions linked to the harmonization and objectification of phenotypic data for the database led us to contact Grégoire Vincke of the company Cytomine to examine the possibilities that algorithms could offer for recording patient aorta measurements and their evolution.

We discovered that the genetic technique currently most widely used in Belgium does not allow a genetic diagnosis of Marfan in all cases, and that the use of Whole Genome Sequencing (WGS) could put an end to the diagnostic odyssey of patients affected by this problem. Generally speaking, our own experience and that of several families lead us to believe that the use of WGS technology could significantly shorten the diagnostic odyssey.[11] in addition to fuelling research programs. With this in mind, we hope to bring P101GM to a successful conclusion and provide the relevant public authorities with what we’ve learned to inform their thinking on the use of the genome.

The time has come…

When we learned about the genome and the needs of researchers, we wondered why the model we’re looking to implement with P101GM didn’t already exist. When we present the P101GM, this question comes up again and again. And we still don’t have a satisfactory answer.

One of the few answers we have was provided by one of the (many) doctors who follow our little boy, when he explained to us that the obstacles were so numerous that the only real progress was made by patient associations.
[12]
that the only real progress was made by patient associations.

Our fate and that of our children is in our hands. If we don’t fight for them and help the doctors who are trying to treat them, no one else will.

Professor Guillaume Jondeau expressed this very well when he described the transformation of ” a drama into a creative force “. And this is also what Stéphanie Delaunay, President of the French Marfans Association, seems to have understood very well when she explains that the P101GM is ” a unifying project for patient associations ” Marfan.

In his commentary on Dessie and Laurens’ article, Professor Bart Loeys confirms that he’s eager to get started because : ” Genetics has undergone a veritable technological revolution in recent years and ” that he believes “ the time has come to use this technology to discover the genetic explanations for the clinical variations between Marfan patients “.

Through P101GM, F101G aims to help researchers like Professor Bart Loeys to advance their work by 10 years, by taming the genome and putting it to work for patients suffering from rare diseases.

“  The future remains uncertain and exciting ” concludes Sam’s mom Dessie.

Romain Alderweireldt
101 Genomes Foundation

[1]       The ” letters ” in question are the famous nucleic bases A (Adenine), C (Cytosine), G (Guanine) and T (Thymine) with which the genome is written.

[2]       Former British Prime Minister David Cameron, whose little boy Ivan suffered from a rare disease, was one of the people behind the project.

[3]       KCE, ” The use of whole genome sequencing in clinical practice : challenges and organisational considerations for Belgium ” available on the KCE website at https://kce.fgov.be/en/the-use-of-whole-genome-sequencing-in-clinical-practice-challenges-and-organisational-considerations

[4]       This is not Whole Genome Sequencing (WGS), but Whole Exome Sequencing (WES). It’s an interesting resource, but unfortunately it doesn’t correspond to today’s golden standard.

[5]       In other words, to help identify the most appropriate therapy for treating patients.

[6]      Available at : https: //www.kbs-frb.be/fr/Activities/Publications/2018/20180704PP

[7]      Read Stephen Lyon Crohn’s story in ” The Lancet ” : https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62279-5/fulltext.

[8]      For example, maraviroc .

[9]      The findings of the ” Resilience Project “, which identified 13 apparently healthy adult individuals who were carriers of pathogenic mutations that should have caused them to develop severe rare diseases that normally develop in childhood, are interesting to consult (CHEN R. et al., ” Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases “, Nature Biotechnology, 34, 531-538 (2016) doi:10.1038/nbt.3514, Received 29 July 2015 Accepted 12 February 2016 Published online 11 April 2016. Available at : https://www.nature.com/nbt/journal/v34/n5/pdf/nbt.3514.pdf ).

[10]      However, genomic information without phenotype can be useful in other fields, such as the study of mutation frequencies in the population (control database), migration history, evolutionary analysis, and so on.

[11]      This was also the observation made in Switzerland by the ” Stiftung für Menschen mit seltenen Krankheiten  |  Foundation for People with Rare Diseases ” in Zurich, which now systematically uses WGS sequencing to make a reliable diagnosis as quickly as possible.

[12]      And the complexity of our country’s institutional system doesn’t help matters, according to this practitioner.