11.2022 - 02.2026

Mnesys an integrated multiscale approach to the study of the nervous system in health and disease

We implemented Hi-C technology, demonstrating in four neurological diseases that balanced and unbalanced structural variants alter the integrity of topologically associating domains, regulatory units of the 3D organization of the genome, with altered gene expression. Using genome/transcriptome and in vitro assays, cryptic variants and variants in non-coding genes were identified in 37% of patients with neurological ciliopathies who tested negative in standard tests. We are developing a pipeline for new disease genes based on phenotype clustering and gene-based burden analysis. We have identified a new neurodevelopmental disorder caused by mutations in FSD1L, which encodes a microtubule-associated protein. At the Mnesys Interdepartmental NSC Facility, medium spiny neurons (MSNs) from iPS cells of patients with del/dup16p11.2 underwent single-cell RNAseq, demonstrating reciprocal variations in MSN neurogenesis kinetics, with a trend towards a ‘direct’ fate.

The introduction of advanced technologies such as Hi-C and innovative strategies for the search for cryptic variants in clinical practice will enable the identification of pathogenic genetic variants that were previously undetectable using conventional methods, bridging the missing heritability gap. This approach has the potential to significantly increase the diagnostic rate and shorten the diagnostic odyssey that afflicts many patients and their families. The validation of these new human cell models of MSN will enable the development of platforms for testing innovative drugs for the treatment of CNV disorders such as 16p11.2 deletions and duplications.

Settori Scientifico Disciplinari

MED/26  NEUROLOGY

Spoke 1 : Neurodevelopment, Cognition and Social Interaction