Approved Research

Effects of copy number variants on the morphological structure of the brain across several neurodevelopmental disorders.

Lay summary

Neurodevelopmental disorders (NDDs) are a group of prevalent and highly heterogeneous pathologies characterized by abnormal brain development resulting in alterations in motor function, learning, language and/or nonverbal communication. Despite considerable advances in gene discovery thanks to large-scale exome and whole genome sequencing studies conducted in the last decade, it is estimated that more than 1,000 genes conferring risk for NDDs within the spectrum have yet to be described. Recently, pathogenic structural variants (SVs), such as deletions, duplications or inversions, have been described as a rare but highly penetrant genetic factor involved in the etiology of different types of NDDs, such as autism, intellectual disability or schizophrenia. This type of variation can affect genomic areas of very different sizes, thus involving a wide range of dose-sensitive genes. On the other hand, previous evidence suggests that these structural variations not only affect the phenotypic manifestation of NDDs but also brain development and consequently brain morphology.  

Thus, meta-analyses of genomic and imaging data from large-scale patient cohorts play a key role in identifying the SVs significantly associated with the morphological manifestations of neurodevelopmental disorders. In this project, we propose to perform a large-scale computational analysis of genomic data and structural MRIs to identify dosage-sensitive critical genes within the SVs that are recurrently modified in patients with NDDs. Furthermore, this study aims to analyze the impact of these variants on brain morphology and to associate SVs with abnormalities that have already been reported in patients with neurodevelopmental conditions, such as cortical thickness, degree of gyration or surface area. The results of the proposed large-scale analysis are likely to provide unprecedented insights into the relationship between genomic variants and the pathophysiology of various NDDs.