Klinefelter syndrome: A neurodevelopmental disease of the synapse

Helen Zhao; Dan Zhou; Yolanda Feng; Gabriel G Haddad

doi:10.1016/j.nbd.2025.107010

Klinefelter syndrome: A neurodevelopmental disease of the synapse

Neurobiol Dis. 2025 Jun 25:107010. doi: 10.1016/j.nbd.2025.107010. Online ahead of print.

Authors

Helen Zhao¹, Dan Zhou¹, Yolanda Feng², Gabriel G Haddad³

Affiliations

¹ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
² School of Biological Science, University of California San Diego, La Jolla, CA 92093, USA.
³ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA; The Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: ghaddad@ucsd.edu.

PMID: 40578768
DOI: 10.1016/j.nbd.2025.107010

Abstract

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome disorder, affecting approximately 1 in every 500 to 650 newborn males. Children with KS display a spectrum of phenotypic manifestations, including abnormal neurocognitive phenotypes. However, due to the limited research focusing on the central nervous system, our understanding of the neurobiology of KS at the cellular and molecular levels remains largely unclear. In this study, we utilized cortical organoids derived from pluripotent stem cells and transcriptomic analysis to explore the mechanisms underlying early brain developmental defects in KS patients. We demonstrate that KS organoids display altered neurogenesis, gliogenesis, and glutamate signaling pathways. We believe these early alterations contribute to the abnormal brain development and later cognitive phenotypes in KS patients.

Keywords: Cortical organoids; Klinefelter syndrome; Neurogenesis; Neurophysiopathology; Stem cells; Transcriptomic analysis.