Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models.

Abstract

Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C experiments identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin three-dimensional (3D) interactions in SMS hiPSCs and 3D cortical organoids. Single-nucleus RNA sequencing of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell-cycle processes, and neuronal signaling. SMS cortical organoids displayed reduced growth, enlarged ventricles, impaired cell-cycle progression, and accelerated neuronal maturation. Through the use of a complementary hiPSC-derived 2D cortical neuronal model, we report that SMS cortical neurons exhibited accelerated dendritic growth, followed by neuronal hyperexcitability associated with reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell-cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.