Abstract
BackgroundCraniosynostosis, defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000–2500 live births. Sagittal craniosynostosis (CS), the most prevalent form of isolated craniosynostosis, is caused by interplay between genetic and perinatal environmental insults. However, the underlying details remain largely unknown.MethodsThe proband (a female monochorionic twin diagnosed with CS), her healthy co-twin sister and parents were enrolled. Obstetric history was extracted from medical records. Genetic screening was performed by whole exome sequencing (WES) and confirmed by Sanger sequencing. Functional annotation, conservation and structural analysis were predicted in public database. Phenotype data of Axin2 knockout mice was downloaded from The International Mouse Phenotyping Consortium (IMPC, http://www.mousephenotype.org).ResultsObstetric medical records showed that, except for the shared perinatal risk factors by the twins, the proband suffered additional persistent breech presentation and intrauterine growth restriction. We identified a heterozygous mutation of Axin2 (c.1181G > A, p.R394H, rs200899695) in monochorionic twins and their father, but not in the mother. This mutation is not reported in Asian population and results in replacement of Arg at residue 394 by His (p.R394H). Arg 394 is located at the GSK3β binding domain of Axin2 protein, which is highly conserved across species. The mutation was predicted to be potentially deleterious by in silico analysis. Incomplete penetrance of Axin2 haploinsufficiency was found in female mice.ConclusionsAxin2 (c.1181G > A, p.R394H, rs200899695) mutation confers susceptibility and perinatal risk factors trigger the occurrence of sagittal craniosynostosis. Our findings provide a new evidence for the gene-environment interplay in understanding pathogenesis of craniosynostosis in Chinese population.
Highlights
Craniosynostosis (CS), defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000–2500 live births [1]
We found that a heterozygous mutation of Axis inhibitor 2 (Axin2) (c.1181G > A, p.R394H, rs200899695) exist in Chinese female monochorionic sisters and their father
We demonstrated that a heterozygous Axin2 (c.1181G > A: p.R394H, rs200899695) mutation was presented in the monochorionic twins and their father, but not in the mother
Summary
Craniosynostosis (CS), defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000–2500 live births [1]. Non-genetic risk factors, like intrauterine constraint, twin gestation, breech delivery, low birth weight, malnutrition, premature delivery, maternal thyroid disorders, gestational diabetes, virus infectious, can either cause or exacerbate craniosynostosis [7, 11,12,13,14]. Several findings demonstrate the interactions between genetic and environmental risk factors contribute to premature fusion of cranial sutures [5, 15], more evidence are still need. Craniosynostosis, defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000–2500 live births. Sagittal craniosynostosis (CS), the most prevalent form of isolated craniosynostosis, is caused by interplay between genetic and perinatal environmental insults.
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