Resolving complex outcomes in 15q13.3 copy number variants using emerging diagnostic and biomarker tools

Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions. Chromosome 15q13.3 contains ~10 genes and is a frequent location for such CNVs. The CNV results in an incomplete penetrance and it is unknown how the same CNV produces different clinical outcomes. Further, there are no human phenotypic or genetic biomarkers associated with this CNV.

Our team of experts has a diverse and multi-faceted approach to develop novel diagnostic biomarkers and to understand disease pathogenesis at the molecular and cellular level.In Aim 1, we will use long-read sequencing to resolve the complete 15q13.3 CNV and identify unknown genetic contributions to clinical phenotypes.

In Aim 2, we identify different brain cell types that contribute to the 15q13.3 microdeletion.

Aim 3 will utilize our large cohort of 15q13.3 CNV patient iPS cells and 3D brain organoids to identify developmental trajectories.

Finally Aim 4 will use patient brain network analysis and identify diagnostic EEG biomarkers that associate with disease severity.In summary, our multi-scale approach will identify novel genetic, molecular, and cellular disease mechanisms for the 15q13.3 CNV rare disorder.

Importantly, our genetic sequencing and patient EEG studies will uncover critical diagnostic biomarkers for future clinical or trial use, laying the groundwork to better clinical predictions and outcomes for patients.