Clinical interest of molecular study in cases of isolated midline craniosynostosis
Open accessAbstract
In some cases of infants with apparently isolated single-suture synostosis, an underlying variant can be found. We aimed to determine the molecular substratum in isolated sagittal and metopic craniosynostosis. To this end, we included all infants who presented isolated midline synostosis (sagittal or metopic) and had undergone surgery at the craniosynostosis national reference center of Lyon University Hospital. All infants were examined by a multidisciplinary team including neurosurgeons, clinical geneticists and neuropsychologist. Among 101 infants tested, 13 carried a total of 13 variants; that is, 12.9% of the infants carried a variant in genes known to be involved in craniosynostosis. Seven infants carried SMAD6 variants, 2 in FGFR2, 1 in TWIST1, one in FREM1, one in ALX4 and one in TCF12. All variants were detected at the heterozygous level in genes associated with autosomal dominant craniosynostosis. Also, neurodevelopmental testing showed especially delayed acquisition of language in children with than without variants in SMAD6. In conclusion, a high percentage of young children with isolated midline craniosynostosis, especially in isolated trigonocephaly, carried SMAD6 variants. The interpretation of the pathogenicity of the genes must take into account incomplete penetrance, usually observed in craniosynostosis. Our results highlight the interest of molecular analysis in the context of isolated sagittal and/or metopic craniosynostosis to enhance an understanding of the pathophysiology of midline craniosynostosis.
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These syndromes are increasingly caused by autosomal-dominant mutations in genes that influence cartilage and bone growth, such as fibroblast growth factor genes 1-3 and the TWIST1 gene.
“These syndromes are increasingly caused by autosomal-dominantly caused mutations in genes that influence cartilage and bone growth, such as mutations in the fibroblast growth factor gene 1–3 on chromosomes 4, 8, 10 and the TWIST 1 gene on chromosome 7 [4, 16, 18].”
From Developments in diagnostic and surgical techniques in children with sagittal suture craniosynostosis: a systematic review spanning the last 30 years (2025) · cites this paper as [18]
The FGFR2 pathway section discusses FGFR2 variants previously described in syndromic craniosynostosis, and the Discussion associates heterozygous TWIST1 variants with Saethre–Chotzen syndrome. The paper does not substantiate an increasing frequency of autosomal-dominant causes or the full FGFR1–3 gene list; its own FGFR2 and TWIST1 findings concern isolated craniosynostosis and include variants classified as having uncertain significance. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVariants in TWIST1, FGFR1, and FGFR2 have been described in sCS, although each accounts for only a minor proportion of cases.
“Variants in TWIST1, FGFR1, and FGFR2 have been described, although each accounts for only a minor proportion of cases [62, 98, 120].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [62]
The Introduction (page unavailable) describes TWIST1 and FGFR2 variants as rare in isolated sagittal craniosynostosis, supporting their description and minor contribution. Neither that passage nor the searched passages on FGFR1 identify FGFR1 variants in these cases, so the claim is unsupported for that gene. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStrong evidence supports a role for the BMP/SMAD pathway in sCS, particularly through SMAD6.
“Strong evidence supports a role for the BMP/SMAD pathway, particularly through SMAD6, whose variants represent one of the most consistent findings in midline NCS [62]; importantly, their penetrance appears to be modified by common regulatory variation near BMP2, supporting a two-locus model rather than a simple monogenic one [76].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [62]
The Discussion reports SMAD6 variants in 7 of 43 children with isolated trigonocephaly and concludes that SMAD6 has a major role in metopic nonsyndromic craniosynostosis. That supports the SMAD6 portion of the claim, but our copy does not establish a broader role for the BMP/SMAD pathway. The later two-locus statement is attached to a different citation and is not judged here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredALX4 is involved in craniofacial development.
“Particularly, ALX4 is involved in craniofacial development [62], anda variant in ALX4 was found associated with a moderate form of frontonasal dysplasia type 1 with minute parietal foramina [126].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [62]
SMAD6 variants represent one of the most consistent findings in midline NCS.
“Strong evidence supports a role for the BMP/SMAD pathway, particularly through SMAD6, whose variants represent one of the most consistent findings in midline NCS [62]; importantly, their penetrance appears to be modified by common regulatory variation near BMP2, supporting a two-locus model rather than a simple monogenic one [76].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [62]
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References 39 · Cited by 18
- Authors
- Di Rocco, F., Rossi, M., Verlut, I., Szathmari, A., Beuriat, P. A., Chatron, N., Chauvel-Picard, J., Mottolese, C., Monin, P., Vinchon, M., Guernouche, S., & Collet, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Lyon 1 Université (FR)
- Corresponding author
- Collet, Corinne
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2023-02-03
- Volume
- 31
- Issue
- 6
- Pages
- 621-628
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC10250395
- OpenAlex
- W4319063531
- Cited by
- 18
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 6
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- sagittal craniosynostosis, metopic craniosynostosis, trigonocephaly, FGFR2, TWIST1, FREM1, ALX4, TCF12, neurodevelopmental outcomes, language delay, incomplete penetrance, genetic variants, molecular diagnosis
- MeSH terms
- Child, Child, Preschool, Craniosynostoses, Humans, Infant
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