Project Description



Unveiling the hidden side of NEUrodevelopmental DIsorder Genetics: a multidisciplinary pathway to new molecular diagnoses by integrating genomic, transcriptomic, and functional analyses.


Neurodevelopmental disorders (NDDs) are a group of disorders caused by the disruption of essential neurodevelopmental processes. NDDs include autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, and epilepsy. Familial NDDs have been instrumental for identifying the contribution of genetic factors to the pathogenesis of NDDs. It has emerged that the phenotypic outcome of NDDs depends upon highly penetrant rare/de novo monogenic variants or common low risk variants leading to multifactorial/polygenic disease. Focusing on the former category, we have been collecting a large survey of 1,100 NDD families analyzed by a-CGH and trio-WES. Despite the implementation of sequencing technologies and the numerous novel NDD-causative genes identified, the percentage of patients who remain undiagnosed at the molecular level is still high (70%). Multiple reasons can account for this: lack of information which leads to missed pathogenic variants (gene unknown at the time of the analysis; scanty information on the variants found); technical restriction of screening methods (low covered regions; missed structural variants); incomplete bioinformatic analyses. Furthermore, many novel genes are still to be annotated and uncommon disease patterns are easily missed. We aim to further clarify the complex genetic bases of NDDs exploiting an integrated multidisciplinary team. A selected group of 50 undiagnosed families will constitute the core of our project: we will perform whole genome sequencing and prepare patient-derived cortical neuronal cell lines generated from induced pluripotent stem (iPS) cells. These cells will be used for tissue-specific transcriptomic profiling neuron-derived, integrated transcriptomic/genomic studies and network and pathway analyses.

Funding sources:

PRIN2020 - Ministero dell’Istruzione, dell’Università e della Ricerca (Roma, IT) - GRANT_NUMBER: 20203P8C3X

Research Team:

The project is coordinated by Prof. Federico Zara, University of Genoa and Gaslini Pediatric Institute, and consist of additional 4 Units lead by Alfredo Brusco, University of Turin and Città della Salute e della Scienza University Hospital, Sandra D’Alfonso, University of Eastern Piemonte, Mauro Fasano, University of Insubria and Andrea Angius, National Research Council (CNR), scientific lead of IRGB-CNR (Monserrato).