Craniofacial microsomia (CFM) is a rare congenital anomaly that involves immature derivatives from the first and second pharyngeal arches. The genetic pathogenesis of CFM is still unclear. Here we interrogate 0.9 million genetic variants in 939 CFM cases and 2,012 controls from China. After genotyping of an additional 443 cases and 1,669 controls, we identify 8 significantly associated loci with the most significant SNP rs13089920 (logistic regression P=2.15 × 10−120) and 5 suggestive loci. The above 13 associated loci, harboured by candidates of ROBO1, GATA3, GBX2, FGF3, NRP2, EDNRB, SHROOM3, SEMA7A, PLCD3, KLF12 and EPAS1, are found to be enriched for genes involved in neural crest cell (NCC) development and vasculogenesis. We then perform whole-genome sequencing on 21 samples from the case cohort, and identify several novel loss-of-function mutations within the associated loci. Our results provide new insights into genetic background of craniofacial microsomia.
Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it’s genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify fifteen significant (P < 5 × 10−8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate nine of them show dramatic expression change during early cranial NCCs development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. SNP-based PRS is significantly associated with CFM (P = 7.22 × 10−58, OR = 3.15, 95% CI 2.74 to 3.63) and the top fifth percentile has a 6.8-fold CFM risk comparing to the tenth percentile. Father’s smoking increases CFM risk as evidenced by interaction parameter of −0.324 (95% CI -0.578 to −0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction and father smoking is a key environmental risk factor for CFM through interacting with genetic factors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.