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Discovery of a new genetic neurodevelopmental disease
A research carried out at the European Institute of Oncology identifies the mechanism responsible for a severe neurodevelopment syndrome

NEUROA recent work of the group led by Prof Testa –University of Milan and European Institute of Oncology (EIO)- identified the pathological mechanism of a severe neurodevelopment syndrome so far unknown but, since today, diagnosable. This disease is due to mutations of Ying Yang, a gene already known in oncology. This study, recently published on The American  Journal of Human Genetics, has been fundedby AIRC, Telethon, ERC, Italian Health Ministry,  Regione Lombardia.


Genetic neurodevelopmental diseases are numerous. Even though they severely affect kids and teenagers, are still largely unknown and, hence, undiagnosed. The lack of a diagnosis represents an insurmountable barrier for a suitable medical care, increasing the feeling of isolation and frustration of the families. Today, one of these diseases has a name, a known cause, and a clear pathological mechanism that in the future may lead to a pharmacological treatment able to, at least, ameliorate the symptoms.



This is the result of the work of Giuseppe Testa -professor of Molecular Biology at the University of Milan and director of the Laboratory of Epigenetics and Stem Cells of EIO in Milan – and the team of Bert de Vries (Radboud University, Nijmegen, Netherlands) published on June 1st on the The American  Journal of Human Genetics and funded by AIRC, Telethon, ERC, Italian Health Ministry,  Regione Lombardia.


The researchers –Michele Gabriele, Anneke T. Vulto-Van Silfhout, Pierre Luc Germain and Alessandro Vitriolo are the first authors of the paper– discovered that YY1 gene, whose role is well known in oncology and in developmental biology, is also the cause of a neurodevelopment syndrome characterized by intellectual disabilities and congenital malformations, classically defined “YY1 Aplo-insufficiency syndrome”.


YY1 has a crucial role in embryogenesis, and its mutations have been already associated with the onset of different tumors, among which breast and prostate cancer. The name, Ying Yang, is due to its typical feature of “Janus-faced”: YY1, indeed, can activate or inactivate many other genes according to the cell context and environmental stimuli, modulating its own function both in physiological conditions and in the onset of pathological processes such as carcinogenesis, when mutations occur in adults.


This study showed that when mutations in YY1 gene occur, instead, at the beginning of development, YY1 Aplo-insufficiency syndrome develops. Particularly, this work clarified the mechanism of action of these mutations, by altering in patients’ cells gene expression and chromatin acetylation (the physiological chemical modification of the DNA responsible for the acquisition of a particular rolled up DNA conformation inside the cells). Acetylation of histones (protein complexes structuring DNA conformation) is a key mechanism modulating genes activity, which is often altered in carcinogenesis. Drugs able to inhibit or favor acetylation already exist and many of these are already in clinical trials for many tumor types. Therefore, the discovery of an acetylation deficit in patients with mutations in YY1 translates, firstly, into an immediate possibility of disease diagnosis and, secondly, opens up a concrete possibility to test, in the future, these acetylation modulators as therapeutic approaches. At the moment, this discovery already represents a great progress at the clinical level for the world of rare genetic diseases: many parents, indeed, find themselves completely lonely and powerless facing symptoms that, even though evident in their children, nobody can link to a known disease.


“Genetics and particularly genome sequencing performed through innovative Next Generation Sequencing Technology, is giving new hopes to these families, because the diagnosis is the first step towards a suitable care and, even before, towards the awareness of the disease’s cause,  representing a huge relief for the families involved” says Prof Testa.


Importantly, this study confirms that some genes already known for their roles in tumor formation may be also at the origin of genetic diseases of intellectual development.


“YY1 – states Prof Testa – is a paradigm in this story of “double identity” of some genes: a line of interpretation opening endless new possibilities of research”.


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