A Gene-Network Discovery Approach to Structural Brain Disorders

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Project Summary/Abstract Lissencephaly is a rare developmental disorder characterized by absence or simplification of brain convolutions. With no available cure, it leads to significant health burden of developmental delay, intellectual disability, and seizures. While introduction of next-generation DNA sequencing offered unprecedented opportunities for gene discovery in human disorders, leading to the identification of an array of lissencephaly-associated genes, approximately a fifth of patients with lissencephaly still lack genetic diagnosis. Gene discovery in Mendelian disorders is hampered by locus and phenotypic heterogeneity and thus, a systems-level analysis complemented with mechanistic characterization of candidate variants is warranted. In the past decade and a half, we have identified and functionally characterized multiple genes whose disruption is associated with malformations of the human cerebral cortex. We propose to utilize patient- derived stem cell and embryonic mouse models to characterize the role of the PIDDosome protein complex in human brain development and understand how its malfunction can cause lissencephaly. We also propose to perform gene- burden and co-expression analyses to inform characterization of novel genes and pathways involved in lissencephaly through modeling in organoids. We will use patient and control keratinocytes to generate induced pluripotent stem cells and 2D and 3D neural derivatives to define the molecular and cellular consequences of PIDD1 mutations, accompanied by in vivo mouse models of PIDD1 loss during neurodevelopment. We will perform gene network-based analysis of human brain development and mutation burden analysis at the gene and pathway level of 120 lissencephaly patients with available whole-exome sequencing data to identify and prioritize novel causal genes for lissencephaly. Our multi- faceted approach is expected to reveal shared molecular pathways and affected cell types that are perturbed during human fetal neurodevelopment leading to the onset of lissencephaly in a genetically heterogenous background, also providing an analytical framework for variant prioritization in large-scale genomic investigation of human disorders.