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Clinical interest of molecular study in cases of isolated midline craniosynostosis

European Journal of Human Genetics (2023)Cite this article

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Abstract

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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Fig. 1: Transcription analysis.
Fig. 2: Distribution of children with or without a variant according to their developmental level, below or under the 50th percentile.

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Acknowledgements

We thank Ms Stephanie Serre for her help in the preparation of the manuscript. We are grateful to the patients and their families who participated to this study.

Funding

No specific funding.

Author information

Authors and Affiliations

  1. Department of Pediatric Neurosurgery, French Referral Center for Craniosynostosis, Hôpital Femme Mère-Enfant Hospices Civils de Lyon, University of Lyon, INSERM 1033, Lyon, France

    Federico Di Rocco, Isabelle Verlut, Alexandru Szathmari, Pierre Aurélien Beuriat, Carmine Mottolese, Matthieu Vinchon & Sofia Guernouche

  2. Department of Genetics, Lyon University Hospitals, INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Lyon, France

    Massimiliano Rossi, Nicolas Chatron & Pauline Monin

  3. Department of Pediatric Cranio-Maxillo-Facial Surgery, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon 1, Lyon, France

    Julie Chauvel-Picard

  4. Department of Genetics, Robert Debré Hospital, Inserm 1132, Université de Paris Cité, Paris, France

    Corinne Collet

Authors
  1. Federico Di Rocco
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Contributions

FDR: conception and design, acquisition of data (AD), analysis and interpretation of data and writing original draft. MR: AD, analysis and interpretation of data, manuscript revising, IV: AD, analysis and interpretation of data, manuscript revising. AS: AD, NC: AD, PAB: AD, JCP: AD, PM: AD, CM: AD, MV: AD, SG: AD, analysis and interpretation of data,manuscript revising, CC: AD, conception and design, analysis and interpretation of data and writing original draft.

Corresponding author

Correspondence to Corinne Collet.

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Competing interests

The authors declare no competing interests.

Ethical approval

The molecular analysis was approved by the French ethics committee (no. IRB00011687; College de neurochirurgie IRB #1: 2022/05) and was performed after parents gave signed informed consent for genetic testing.

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Di Rocco, F., Rossi, M., Verlut, I. et al. Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01295-y

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