Do you know what Schaaf-Yang syndrome is? Probably not, as it is an ultra-rare disease, with around a hundred diagnosed cases around the world. Its frequency is so low because it requires a series of unusual genetic alterations: out of the approximately 24,000 genes present in our genome, it is MAGEL2 the one that must be mutated. Furthermore, this mutation must occur in the paternal chromosome, since the maternal allele is silenced due to imprinting, a stable chemical modification in DNA that prevents the expression of a gene. Finally, the mutation must be truncating, generating a protein that is shorter than normal.
What symptoms characterize this syndrome? Over the years, a characteristic phenotype of patients with truncating mutations in the MAGEL2 gene has been consolidated. The main symptoms include decreased muscle tone in neonates, feeding difficulties during childhood, developmental delay, respiratory problems, and hypogonadism. Besides, another characteristic condition among individuals with Schaaf-Yang syndrome is the presence of joint contractures, which often occur in the phalanges, elbows, or knees. Similarly, although in many cases its assessment is not possible due to a severe intellectual disability, patients usually have some degree of autism .
It is sometimes difficult to distinguish Schaaf-Yang syndrome’s symptoms from those of other syndromes, such as Prader-Willi. This disease not only presents a similar phenotype but also has a similar genetic cause, involving MAGEL2. However, in this case, the protein is not truncated, it is absent. In fact, in Prader-Willi syndrome, neither MAGEL2 nor those genes present in an area of chromosome 15 called the Prader-Willi critical region are expressed . With this in mind, it would be expected that the consequences of this syndrome would be much worse than those of Schaaf-Yang, but surprisingly, this is not the case, and the symptoms are less severe in most patients. But, how is it possible that having just one part of the gene is more damaging than not having it at all? There are different theories regarding this. The first one is that the protein produced in patients with Schaaf-Yang syndrome, being shorter than normal, could acquire new pathogenic effects. The second one is that in patients with Prader-Willi Syndrome, a mechanism prevents the silencing of the maternal chromosome and allows its expression, producing small amounts of protein. Almost undetectable, but sufficient to perform part of its function and alleviate the symptoms of these patients .
However, despite these hypotheses, there is still a lack of knowledge about Schaaf-Yang syndrome. This also contributes to the odyssey that families go through when it comes to achieving a correct diagnosis. The importance of having such a diagnosis lies in the fact that it opens a path to connect with other families, which not only is a way of finding emotional support but is also a source of information about experiences, palliative treatments, and evolution of pathology. In addition, there is a component of great value in achieving a good diagnosis, since in many cases it results in an improvement in the treatment and management of the patient.
Thanks to the efforts of the scientific community, including those of our research group, the gene that causes Schaaf-Yang syndrome has already been identified. Therefore, nowadays the key to an accurate diagnosis lies in sequencing the whole exome or the patient’s MAGEL2 gene to find out which mutation is present. The identification of the causing mutation of a rare disease is also the starting point in the discovery of therapeutic targets and specific drugs for the syndrome, which is extremely important. In fact, although palliatives and early intervention improve the life of patients with Schaaf-Yang, there is still no specific treatment for this syndrome.
In the Human Molecular Genetics research group at the University of Barcelona, we focus on performing functional studies and developing new research strategies regarding this disease. Thanks to the collaboration and direct contact with families, we can count on a cohort of individuals diagnosed with Schaaf-Yang Syndrome. Furthermore, their enthusiasm and generosity have enabled us to work with patients’ skin cells. These cells are called fibroblasts and are useful to study the cellular pathways affected by the mutations in a more personalized way. The experiments carried out on these cells have provided us with great results and for that, we are extremely grateful to families.
Having already worked with fibroblasts, the next goal we have is to obtain neurons, which are the most useful cells to study Schaaf-Yang Syndrome. However, they cannot be obtained directly from patients. So how do we intend to acquire them? Generating them from patient’s skin cells. The basic idea would be to reprogram fibroblasts and transform them into a type of stem cells called iPS. These iPS can be differentiated to neurons, which are then characterized and analyzed. By studying neurons, it would also be possible to explore new biomarkers, more robust than those we have already identified. Having a good biomarker is essential to understand the effect of mutations and it would allow us to evaluate potential therapeutic approaches, the development of which is of vital importance.
Although the journey to finding a cure for a rare genetic disease is a long one, the efforts made by patient associations, as well as their funding, have paid off. That is why maintaining close collaboration between families and researchers is the key to continue working. There are still some unresolved questions about Schaaf-Yang Syndrome, and together we will figure them out.
 McCarthy, John, Philip J. Lupo, Erin Kovar, Megan Rech, Bret Bostwick, Daryl Scott, Katerina Kraft, et al. 2018. “Schaaf-Yang Syndrome Overview: Report of 78 Individuals.” American Journal of Medical Genetics, 176A:2564–2574. https://doi.org/10.1002/ajmg.a.40650.
 Fountain, Michael, and Christian Schaaf. 2016. “Prader-Willi Syndrome and Schaaf-Yang Syndrome: Neurodevelopmental Diseases Intersecting at the MAGEL2 Gene.” Diseases. 4,2. https://doi.org/10.3390/diseases4010002.Tacer, Klementina Fon, and Patrick Ryan Potts. 2017. “Cellular and Disease Functions of the Prader-Willi Syndrome Gene Magel2.” Biochemical Journal. 474(13):2177-2190. https://doi.org/10.1042/BCJ20160616.
Article by Monica Centeno, student of Biochemistry (UB) and member of the research group led by Dr. Susanna Balcells and Daniel Grinberg (UB, CIBERER)