Poster #50: Hannah McGinty

Evidence for Shared Developmental Signaling Landscapes Between Craniosynostosis and Idiopathic Hypogonadotropic Hypogonadism

Hannah McGinty, BS Candidate¹˒⁴; Ravikumar Balasubramanian, MBBS, PhD²; Erica E. Davis, PhD¹˒³; Ahmet Sacan, PhD⁴. ¹Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago; ²Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital; ³Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University; ⁴School of Biomedical Engineering, Science & Health Systems, Drexel University.

Background: Craniosynostosis (CS) and idiopathic hypogonadotropic hypogonadism (IHH) are developmental disorders with incompletely understood shared genetic mechanisms. We investigated pleiotropic relationships between CS and IHH using comparative pathway and phenotype enrichment analyses. Methods: Gene lists for CS and IHH were created through literature curation of human and mouse phenotypes. CS and IHH gene sets were analyzed using enrichment and network-based approaches (Enrichr, PxEA). Analyses were performed across Human Phenotype Ontology, Gene Ontology Biological Processes, Reactome Pathways, and DisGeNET databases using an adjusted p-value threshold of 0.01. Terms common to both CS and IHH were identified. Additionally, we performed pathway-guided gene prioritization to identify new candidate genes contributing to shared CS-IHH developmental pathways. Results: CS and IHH demonstrated significant overlap in developmental signaling and growth-related pathways. The analysis recovered known shared biology involving FGFR1-associated signaling, while also identifying additional shared enrichment in insulin, PI3K, and receptor tyrosine kinase signaling. Phenotype enrichment analysis identified the expected skeletal and reproductive phenotypes. Enrichment analysis of the five genes shared between CS and IHH (TCF12, FGFR1, SPRY4, GLI3, ZIC1) identified highly significant enrichment for multiple craniosynostosis phenotypes and syndromes, primarily driven by TCF12, ZIC1, and GLI3. Additional enrichment was observed for craniofacial and neurodevelopmental features such as frontal bossing, intracranial hypertension, and visual field defects. Exploratory reverse enrichment of genes using the terms commonly enriched for both CS and IHH identified several potentially novel shared candidate genes, including KIF7, RPGRIP1L, SPRY2, WNT5A, FGFR4, and SULF1. This enrichment was driven by the shared pathways including FGF, PI3K, MAPK, suggesting convergent disruption of craniofacial and neuroendocrine developmental programs. Conclusions: Enrichment across both the aggregate disease-associated gene sets and the list of five genes causally shared between CS and IHH suggests that overlapping mechanisms in developmental signaling and craniofacial patterning may contribute to pleiotropic disease biology.