The Clinical and Translational Bioinformatics Group at Vall d'Hebron Institute of Research (VHIR) has participated in two large international studies, published in Science Advances and Nature Communications, that have unraveled the inherent mechanisms of two different neurodevelopmental disorders of genetic origin. The two studies have been led by the Children's Hospital of Philadelphia and have involved the collaboration of a large multinational team of scientists and healthcare professionals. Each focused on a specific gene, EZH1 and KMT5B, to discover how their mutations cause disruptions in the neurological growth. In both cases, the group under the direction of Dr Xavier de Cruz has used data analysis and structural modeling techniques to uncover the specific mechanisms that cause neurodevelopmental dysfunction in patients with mutations in these.

Computational modelling of 14 variants to understand the effect of mutations

The first study focused on the KMT5B gene, one of the enzymes that catalyse the transfer of methyl groups from S-adenosylmethionine (SAM) to histones (key chromatin proteins). Mutations of this gene are associated with a number of neurodevelopmental anomalies manifesting as global delay, macrocephaly and autism. The study has performed the most exhaustive analysis to date of people with this pathology. It has identified previously unnoticed clinical features such as hypotonia, or muscle weakness, and congenital heart defects. By shedding light on these previously unknown facets, this study creates a more complete picture of this disorder.

The VHIR team designed and performed the computational analysis of 14 different missense variants (single amino acid mutations) of KMT5B. The results obtained have allowed the discovery of the molecular mechanisms by which these mutations prevent the correct function of the protein. Dr De Cruz, head of the Clinical and Translational Bioinformatics group at VHIR, explains that "the results are a crucial link between genetic studies and clinical results for understanding neurological disorders related to the KMT5B gene".

Understanding the impact of missense genetic variants in neurodevelopmental disorders

The second study investigated the role of the chromatin regulator EZH1. The study detailed the impact of the gene's mutations on neurogenesis and demonstrated the involvement of EZH1 variants in dominant and recessive neurodevelopmental disorders. The research team stresses that the discovery underlines the importance of chromatin regulation in neurodevelopment.

The creation of computational models of the EZH1 gene variants, again designed and executed by VHIR's Bioinformatics group, suggested that the mutations affected the gene's function. Especially in its interaction with other molecules and, in particular, with nucleosomes, a specific part of chromatin. These modifications might be responsible for critical changes in the pattern of gene expression in the neuronal development of the affected person.

These two studies represent a significant advance in Dr de Cruz's research on the molecular impact of missense genetic variants in neurodevelopmental disorders. Along with a previous study published in Science Advances on the role of H3.3 variants, the three studies form a cumulative body of knowledge that paves the way for the development of medical interventions aimed at alleviating the challenges faced by people affected by these disorders. Dr Natalia Padilla, researcher in the Clinical and Translational Bioinformatics group, comments that "the group's continued participation in multicentre and international initiatives led by the Children's Hospital of Philadelphia, illustrates our ability to address complex modelling demands in pioneering healthcare projects".

This research has been made possible thanks to grant PID2019-111217RB-I00 from the Spanish Ministry of Science and Innovation awarded to Dr De Cruz.