Copy number variations (CNVs) of the human 16p11.2 genetic locus are associated with a number of neurodevelopmental and psychiatric conditions. Autism and macrocephaly are more common in individuals with 16p deletions (16pdel), while schizophrenia and microcephaly are more common in individuals with 16p duplications (16pdup). Previous studies of 16p11.2 CNVs have implicated deficits in cortical neuron architecture, connectivity and function during brain development. In addition, several molecular pathways from the 16p11.2 region modulate energy and lipid metabolism.

To delve deeper into the metabolic effects of 16p11.2 CNVs, Mirjana Maletić-Savatić and colleagues performed transcriptome and metabolome studies on brain organoids derived from CRISPR-Cas9-induced 16pdel and their isogenic controls. Her team found significant changes in key mitochondrial and enzyme transcripts that directly correlated with observed changes in the metabolome and lipidome, and unpublished data suggest that 16pdel leads to complex metabolic disruptions that might contribute to the observed functional neuronal network phenotypes. Maletić-Savatić thus hypothesizes that 16p11.2 CNVs regulate pathways associated with lipid synthesis and metabolism that together might cause deficits in membrane integrity and neuronal transmission.

To test this hypothesis and advance understanding of the factors that contribute to 16p11.2 CNV pathology, Maletić-Savatić’s lab proposes to investigate the impact of 16p11.2 CNVs on transcriptome-metabolome coupling and membrane integrity using brain organoids derived from induced pluripotent stem cell lines from Simons Searchlight participants, isogenic and non-isogenic neurotypical controls. Results from this study are expected to shed light on new molecular targets that may lead to the development of novel therapeutics for 16p11.2 CNV conditions.