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Completing Renewal 

Abstract for P01HD70494 Renewal

Structural brain defects (SBDs) refer to a collection of individually rare clinical conditions usually due to single gene mutations, where brain morphology and function is disrupted. SBDs occur when the normal cell proliferation, migration, and/or organization is perturbed. Various genetic, ischemic, infectious, and toxic insults may cause brain malformation. Neuroimaging has come to encompass a wide array of modalities that can be combined to gain complementary information regarding the brain’s structural, functional and metabolic dimensions in the pathologic state.

The goal of our Program is to uncover causes and mechanisms of SBDs of metabolic origin, and identify potential treatments. We focus on neurometabolism due to the frequency of these conditions, and because there is the potential for early treatment intervention by correcting metabolic pathways. Many inborn errors of metabolism (IEM) are associated with SBDs that may add diagnostic specificity to an otherwise nonspecific clinical presentation. Structural brain abnormalities may be present in up to 14% of patients with congenital metabolic disease, and while practitioners tend to think of metabolic conditions presenting only after birth, there are many conditions in which metabolism is critically disrupted in utero, interfering with the key developmental steps in brain development.

Despite advances in NGS, still half of families that undergo whole exome sequencing cannot receive a molecular diagnosis. To improve upon this, we focus on the identification of mutations from a collection of families with elevated consanguinity where DNA and cells lines are established, a massive and still growing database of whole exome, whole genome and RNA sequencing, and already established IPSCs to both improve diagnosis and advance understanding of molecular mechanism. We propose to model these conditions using brain organoids and mouse models, and to solve cases where exome has not yielded cause, and to develop a mechanistic understanding of disease in cases where the gene is already identified in humans to cause disease, and where treatments might be possible.

Narrative for HD70494 Renewal

The goal of this Project is to uncover the causes and mechanisms of structural brain defects of metabolic origin and to identify potential treatment, contributing to enhanced health of children. We focus on identifying mutations in metabolic pathways by utilizing our unique cohort of consanguineous families, integrating whole exome, whole genome and RNA sequencing strategies and modeling disease in brain organoids and mouse.

Project 1. PI Joseph Gleeson. Genetic dissection of human structural brain disorders form inbred populations.
Project 2. Alysson Muotri. Modeling genetics SBDs in stem cells and organoids to understand mechanism.
Project 3. Susan Ackerman. Mouse models of human structural brain defects: Metabolism and Modifiers

Core 1. Joseph Gleeson. Administrative Core
Core 2. Kristen Jepsen. High throughput sequencing genomics core
Core 3. Vineet Bafna. Bioinformatics core for NGS sequence analysis