A higher proportion of craniosynostosis genes are cancer driver genes

Abstract

Craniosynostosis (CS) is a congenital abnormality deformity with a heterogeneous genetic contribution. There were previously two attempts to collect genes that are genetically associated with craniosynostosis and some related syndromes with 57 (Twigg and Wilkie, 2015), 39 (Goos and Mathijssen, 2019) genes identified, respectively. We expanded this list of craniosynostosis genes by adding another 17 genes with an updated literature search, plus 7 more from a recent update (Tooze et al., 2023), leading to a combined of 120 genes. These genes are shown to be more likely to be intolerant to functional mutations. Of these 120 craniosynostosis genes, 32 (26.7 % vs. 3.5 % baseline frequency) are cancer driver genes, a 7.6-fold enrichment. The cancer-craniosynostosis connection is further validated by an over-representation analysis of craniosynostosis genes in KEGG cancer pathway and several cancer related gene-sets. Many cancer-craniosynostosis overlapping genes participate in intracellular signaling pathways, which play a role in both development and cancer. This connection can be viewed from the “oncogenesis recapitulates ontogenesis” framework. Twenty-five craniosynostosis genes are transcription factor genes (20.8 % vs. 10.3 % baseline), and craniosynostosis genes are also enriched in targets of certain transcription factors or micro RNAs.