Unveiling the hidden side of NEUrodevelopmental DIsorder Genetics (NEUDIG): a multidisciplinary pathway to new molecular diagnoses by integrating genomic, transcriptomic, and functional analyses.
ProjectNeurodevelopmental 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 analysed 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 (e.g., novel
imprinting disorders, TAR-like phenotype, TADopathies).
We aim to further clarify the complex genetic bases of NDDs exploiting an integrated multidisciplinary team. We will start from the harmonization and re-analysis of our trio whole-exome sequencing dataset. We will
combine several variant filtering options and evaluate incomplete penetrance/variable expressivity and missed CNVs. A selected group of 50 undiagnosed families (quad) 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 and integrated transcriptomic/genomic studies. We will perform network and pathway analyses exploiting up-to-date machine learning models for variant interpretation. The final task of our project will
involve functional characterization of selected variants by genetic, biochemical, cellular and epigenomic assays.
We expect to identify new genes and genomic mechanisms involved in NDDs. In addition, the present proposal will produce significant deliverables: a unique collection with genomic and phenotypic information for NDDs,
standardized procedures to extract maximal information from genomic data, allowing iteration and sharing among different centers; a valuable set of iPS cell lines from patients with NDDs that will be made available to the
scientific community, a comprehensive and expandable functional map of molecular pathways involved in NDD, protocols and materials for a functional diagnostic pipeline to interpret unconventional genomic variants
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 analysed 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 (e.g., novel
imprinting disorders, TAR-like phenotype, TADopathies).
We aim to further clarify the complex genetic bases of NDDs exploiting an integrated multidisciplinary team. We will start from the harmonization and re-analysis of our trio whole-exome sequencing dataset. We will
combine several variant filtering options and evaluate incomplete penetrance/variable expressivity and missed CNVs. A selected group of 50 undiagnosed families (quad) 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 and integrated transcriptomic/genomic studies. We will perform network and pathway analyses exploiting up-to-date machine learning models for variant interpretation. The final task of our project will
involve functional characterization of selected variants by genetic, biochemical, cellular and epigenomic assays.
We expect to identify new genes and genomic mechanisms involved in NDDs. In addition, the present proposal will produce significant deliverables: a unique collection with genomic and phenotypic information for NDDs,
standardized procedures to extract maximal information from genomic data, allowing iteration and sharing among different centers; a valuable set of iPS cell lines from patients with NDDs that will be made available to the
scientific community, a comprehensive and expandable functional map of molecular pathways involved in NDD, protocols and materials for a functional diagnostic pipeline to interpret unconventional genomic variants