ABSTRACT
Craniosynostosis (CRS) is a congenital abnormality deformity with a heterogenous genetic contribution. Previously, there are two attempts to collect genes that are genetically associated with craniosynostosis and some related syndromes with 57 (Twigg and Wilkie, 2015) and 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. These genes are shown to be more likely to be intolerant to functional mutations. Of these 113 craniosynostosis genes, 21 (19% vs. 1.5% baseline frequency) are cancer driver genes, a 14-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. Nineteen craniosynostosis genes are transcription factor genes (16.8% vs. 8.2% baseline), and craniosynostosis genes are also enriched in targets of certain transcription factors or micro RNAs.
abbreviations
- CADD
- combined annotation dependent depletion;
- CML
- chronic myelogenous leukemia;
- CNV
- copy number variation;
- CRS
- craniosynostosis;
- FGF
- fibroblast growth factor;
- GDI
- gene damage index;
- GEO
- gene expression omnibus database;
- GO
- gene ontology;
- GS
- gene-set;
- GWAS
- genome-wide association studies;
- HUGO
- Human Genome Organisation;
- IPA
- Ingenuity Pathway Analysis;
- KEGG
- Kyoto Encyclopedia of Genes and Genomes;
- LOEUF
- loss-of-function observed-over-expected upper bound fraction;
- MeSH
- medical subject headings;
- MSigDB
- Molecular Signature Database;
- OR
- odds-ratio;
- PID
- pathway interaction database;
- pv
- p-value of a test;
- RVIS
- residual variation intolerance score;
- SNP
- single-nucleotide polymorphism;
- TDT
- transmission disequilibrium test;
- TGF
- transforming growth factor;
- TF
- transcription factor;