Rare diseases are those that affect a small percentage of the population. Specifically, a disease is classified as rare when it affects less than 5 out of every 10,000 inhabitants. However, there are many people affected by a rare disease of any kind. According to WHO, there are about 7000 rare diseases that affect a 7% of the world population. Only in Spain it is estimated that about 3 million people suffer from some rare disease.
Within these rare diseases, there are some that are even less frequent, such as TRAF7 syndrome. This is an ultra-rare genetic disease that causes intellectual disability, motor delay, short stature, heart defects and a wide variety of facial features1,2. To date, less than 50 cases have been diagnosed around the world1.
Our research group studies a rare syndrome known as Opitz C. Over the years we have gathered a cohort of about 20 affected families. However, it was concluded that this syndrome does not exist as such3. It rather should be considered as a clinical entity without a unique genetic basis, since we identified a different gene as responsible for the disease in each patient. This caused each patient to be re-diagnosed to a more specific rare syndrome according to their genetic diagnosis. Julia, one of the Spanish patients initially diagnosed as Opitz C syndrome, had a mutation in a gene called TRAF7. This change was “de novo“, meaning that it had appeared during her development, and was not present in either her parents or her healthy siblings. This fact, together with the previous information about the TRAF7 gene, indicated that this mutation would most probably be the cause of her pathology. At that time, the TRAF7 gene had not been associated with a disease already. But to know if a mutation causes a certain disease, it is necessary to carry out a series of functional studies that demonstrate that there is a relationship between the mutations and the patient’s clinic. In addition, it is very useful to be able to identify other patients who present mutations in the same gene and study how similar or different they are at clinical level.
One of the great challenges that arise trying to define a novel rare disease (and especially an ultra-rare one) is to find enough cases to establish the defining clinical profile, which helps to identify it. Having a tool that allows doctors and researchers from all over the world to get in touch can make this process much easier. The fact that a researcher can share the genetic and clinical information of one of his/her patients globally, while of course guaranteeing the total privacy of the patient, increases the likelihood of finding more cases that have similar mutations in the same gene and similar physical features. Genematcher website, among others, is a great help in this task, since it allows the sharing of the identified mutation and the main clinical features of a patient, while respecting their privacy4. In our research group, Genematcher has allowed us to contact researchers from all over the world, and after a great collaborative effort, we have managed to bring together a cohort of more than 40 patients with TRAF7 mutations. Being able to study all these patients together allowed us to identify some similar and recurrent physical features among them that define this new pathology, the TRAF7 syndrome, and confirm Julia’s diagnosis. The defined clinical profile of the TRAF7 syndrome presents the following characteristics: intellectual disability, motor delay, a wide variety of characteristic facial features, short neck, heart defects, dysmorphic features and hearing loss, among others. Additionally, we have been able to obtain skin biopsies from some of these patients in order to carry out functional studies on this pathology, with the aim of confirming the causality of TRAF7 mutations. From these biopsies, fibroblasts were obtained to analyze the differences in expression that may exist in some genes compared to individuals who do not suffer this disease. Furthermore, it has allowed us to identify alterations in specific pathways related to neurological and cardiac development, clearly affected in these patients, and therefore improves our understanding of this pathology. This work has been published very recently1.
Once a new rare syndrome has been delineated, it is important to focus on facilitating clinical diagnosis of the future cases that will appear. Aiming to facilitate this diagnosis process, the Face2Gene project was born. The purpose of this project is to create an application that uses artificial intelligence to provide a list of possible syndromes that a patient could suffer based on identified facial features from photographs. The first step to develop this application is to upload photos of patients with a clear genetic diagnosis. This educates the AI (artificial intelligence) system and creates a syndrome facial composite, which is a kind of image of the facial features characteristic of each syndrome. The objective is to obtain photos of many patients of different genetic diagnoses in order to obtain facial composites of each syndrome that are as close to reality as possible. Therefore, involvement of families is key to the success of this project, the more families we get to participate by giving consent to upload photos or uploading them themselves, the better AI will be to make the right diagnosis. Once the system is trained enough, doctors will be able to upload a frontal photograph of the face and a series of clinical features of the patient they are trying to diagnose and Face2Gene will suggest a number of possible syndromes based on the patient’s features. This tool is already being used in several hospitals, although it’s still in the learning phase. When it works optimally, it will be a good tool to complement the information obtained by genetic analysis, shortening the time needed to make the diagnosis of a rare disease.
The average time it takes for a patient to be diagnosed with a rare disease is usually about 5 years. This causes great suffering to families, who while not having a clear diagnosis feel a great sense of loneliness and helplessness. Added to this are the fear that the patient is being treated inappropriately and the bureaucratic problems that may arise from not having a diagnosis (difficulty in obtaining help for the application of certain therapies such as speech therapy, physiotherapy …). If the time to make the diagnosis is shortened, in some way we will also reduce the stress on the families. Furthermore, once the patient is correctly diagnosed, they can contact other affected families thanks to social networks to talk about their day to day life, therapies, side effects, and, in general, support each other. Increased contact between families can also favor the emergence of associations for these rare diseases5. In this way, they can exert more pressure for research on a rare disease and give more visibility to the syndrome. In addition, families will no longer feel so isolated and will be able to receive legal and psychological support.The road to find a cure for a rare genetic disease is a long one. Currently, our research group is working to understand how the mutations that occur in the TRAF7 gene cause the physical features characteristic of TRAF7 syndrome. One of the first issues we must solve is whether the pathogenic mutations in TRAF7 cause the gene to function too little (loss of function) or too much, or to acquire new functions (gain of function). When we solve this issue, we will take a very important step towards the treatment of the disease, since we will be able to start investigating possible therapeutic strategies to fight it. I hope that the experimental work that I have done in my master project can help to solve this very important issue about TRAF7 syndrome.
TRAF7 TRIBE at Facebook is a great point for families to connect with other TRAF7 patients worldwide.
1. Castilla-Vallmanya, L. et al. Genetics in Medicine Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. Genet. Med. (2020).
2. Tokita, M. J. et al. De Novo Missense Variants in TRAF7 Cause Developmental Delay , Congenital Anomalies , and Dysmorphic Features. Am. J. Hum. Genet. 103, 154–162 (2018).
3. Urreizti, R., Grinberg, D. & Balcells, S. Expert Opinion on Orphan Drugs C syndrome – what do we know and what could the future hold ? Expert Opin. Orphan Drugs 7, 91–94 (2019).
4. Sobreira, N., Valle, D. & Hamosh, A. GeneMatcher : A Matching Tool for Connecting Investigators with an Interest in the Same Gene. Hum. Mutat. 36, 928–930 (2015).
5. Olga, M., Sauces, S. & Ruiz-callado, R. Las comunidades virtuales de pacientes con enfermedades raras . Análisis de su influencia en la toma de decisiones y en el cambio de conductas relacionadas con el proceso de enfermedad Virtual communities of patients with rare diseases . Analysis of their. Salud Uninorte. Barranquilla (Col.) 34, 160–173 (2018).
This article has been written by Miguel Subías, Biotechnology graduate (UB) and student of the Genetics and Genomics master’s degree at the UB. Currently in the research group of Dr. Susanna Balcells and part of CIBERER at Genetics, Microbiology and Statistics department (UB).
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