An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family
Open accessAbstract
Background: 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. However, the underlying details remain largely unknown. Methods: The 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). Results: Obstetric 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. Conclusions: Axin2 (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.
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Increasing evidence implicates WNT/β-catenin signalling through AXIN1, AXIN2, and RUNX2 in sCS, suggesting that dysregulated osteoblast differentiation may be a recurrent biological mechanism.
“Similarly, increasing evidence implicates WNT/β-catenin signalling through AXIN1, AXIN2, and RUNX2, suggesting that dysregulated osteoblast differentiation may be a recurrent biological mechanism in sCS [58, 105, 118, 121].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [118]
Discordant phenotypes in genetically identical twins carrying the same variant, as reported for AXIN2 and ERF, suggest that genetic predisposition alone may not fully determine the phenotype and that additional modifiers are likely involved.
“The observation of discordant phenotypes in genetically identical twins carrying the same variant, as reported for AXIN2 and ERF, further suggests that genetic predisposition alone may not fully determine the phenotype and that additional modifiers are likely involved [63, 118].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [118]
Maternal occupation can increase exposure of metals and polycyclic aromatic hydrocarbons (PAHs) to the foetus.
“Another important factor that can influence skull growth and correct bone differentiation is maternal occupation, which can increase the exposure of metals [114, 118] and polycyclic aromatic hydrocarbons (PAHs) to the foetus [89].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [118]
The citation [89] is attached to the claim about fetal exposure to PAHs, not the separately cited claim about metals. The Discussion identifies breech presentation and intrauterine growth restriction as environmental insults, but our copy does not address maternal occupation or PAH exposure (searched: polycyclic aromatic hydrocarbons, PAHs, maternal occupation, occupational exposure). (LLM, conf=0.76)
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“Another important factor that can influence skull growth and correct bone differentiation is maternal occupation, which can increase the exposure of metals [114, 118] and polycyclic aromatic hydrocarbons (PAHs) to the foetus [89].”
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- Authors
- Xu, J., Yan, Q., Song, C., Liang, J., Zhao, L., Zhang, X., Weng, Z., Xu, C., Liu, Q., Xu, S., Pang, L., Zhang, L., Sun, Y., Wang, G., & Gu, A.
- Affiliations
- State Key Laboratory of Reproductive Medicine (CN)
- Nanjing Children's Hospital (CN)
- Shanghai Institute of Planned Parenthood Research (CN)
- Jiangsu Province Hospital (CN)
- Nanjing Medical University (CN)
- Corresponding author
- Wang, Gang
- Gu, Aihua
- ORCID
- Venue
- Hereditas
- Published
- 2021-06-16
- Volume
- 158
- Issue
- 1
- Pages
- 20-20
- ISSN
- 0018-0661 (ISSN-L)
- 1601-5223
- PMC
- PMC8210395
- OpenAlex
- W3167495116
- Cited by
- 4
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2022: 1
- FWCI
- 0.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Hereditas (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- the Jiangsu Students’ Platform for Innovation and Entrepreneurship Training Program (201810312036Y)
- the Opening Foundation of State Key Laboratory of Reproductive Medicine (SKLRM-K202009)
- National Natural Science Foundation of China (81703261)
- Natural Science Foundation of Jiangsu Province (BK20171060)
- Natural Science Foundation of the Jiangsu Higher Education Institutions of China (17KJB330002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- sagittal craniosynostosis, Axin2, monochorionic twins, perinatal risk factors, fetal growth restriction, breech presentation, haploinsufficiency, gene-environment interaction, Chinese population
- MeSH terms
- Exome Sequencing, Animals, China, Craniosynostoses, Female, Humans, Mutation, Risk Factors, Twins, Monozygotic, Mice, Knockout, Asian People, Mice, Axin Protein
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