# A Gene-Network Discovery Approach to Structural Brain Disorders

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $684,946

## Abstract

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.

## Key facts

- **NIH application ID:** 10734863
- **Project number:** 1R01HD110693-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kaya Bilguvar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $684,946
- **Award type:** 1
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734863

## Citation

> US National Institutes of Health, RePORTER application 10734863, A Gene-Network Discovery Approach to Structural Brain Disorders (1R01HD110693-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10734863. Licensed CC0.

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