Iron deficiency and neuropsychiatric disease risk in 3q29 deletion syndrome

Recurrent genomic deletion at chromosome 3q29 (3q29Del) is associated with developmental delay (DD), ADHD, autism spectrum disorders (ASD), and is the strongest known genetic risk factor for schizophrenia (SCZ). However, the phenotypic spectrum associated with 3q29Del is variable and broad. Most individuals have been found to have clinically significant neuropsychiatric impairment, but it is not yet clear why some individuals are much more severely affected than others. The variable expressivity of this important variant suggests environmental factors may influence outcomes. In this R21 project, we propose to assess iron deficiency (FeD) as an environmental factor that may strongly impact 3q29Del clinical outcomes. The 3q29Del results in heterozygosity of 21 protein-coding genes including TFRC, which encodes the transferrin receptor (TFRC). TFRC is the primary cell surface receptor for iron-bound transferrin and is critical for cellular iron import. Iron deficiency is the most common nutrient deficiency worldwide, and recent reports indicate it continues to be highly prevalent in the United States, particularly in children, adolescents, and during pregnancy. While it is well established that childhood FeD can negatively impact neurodevelopment and increase risk for ADHD, ASD, DD, and SCZ, the mechanisms of these processes in human neural cells are not well understood. Innovative in vitro modeling techniques such as 3D brain organoids open new possibilities to causally test the impact of nutrient deficiencies such as FeD on certain aspects of human neurodevelopment. Our preliminary studies indicate that individuals with 3q29Del have more than 10-fold increased risk for anemia. Additionally, 3q29Del cells were found to contain less iron than control cells and had severely reduced viability and mitochondrial function in FeD-like conditions. Together these data indicate that 3q29Del individuals are at extraordinarily high risk for iron deficiency, which may disrupt key neurodevelopmental processes. The aims of this proposal are to (1) determine the risk for FeD and connection to neuropsychiatric phenotypes in individuals with 3q29Del and (2) to model the effects of iron deficiency on the developing human cortex in vitro. We will expand an active R01 project to collect new data related to history of iron deficiency and/or anemia in 3q29Del study participants using gold standard instruments to measure multiple domains of cognitive function, prodromal and psychosis signs. We will measure mitochondrial function in human forebrain-like cortical neurons exposed to FeD-like conditions from both neurotypical control and 3q29Del backgrounds. Lastly, we will determine the effects of FeD-like conditions on human cortical organoid development. These studies will illuminate effects of iron deficiency on the developing human cortex and test environmental interactions with an important neuropsychiatric risk variant. Project Number: 1R21MH141697-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Ryan Purcell | Institution: VIRGINIA POLYTECHNIC INST AND ST UNIV, BLACKSBURG, VA | Award Amount: $456,864 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CN-U (82)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11372578