Clinical interest of molecular study in cases of isolated midline craniosynostosis

• Published in: European journal of human genetics : EJHG Vol. 31; no. 6; pp. 621 - 628
• Main Authors: Di Rocco, Federico, Rossi, Massimiliano, Verlut, Isabelle, Szathmari, Alexandru, Beuriat, Pierre Aurélien, Chatron, Nicolas, Chauvel-Picard, Julie, Mottolese, Carmine, Monin, Pauline, Vinchon, Matthieu, Guernouche, Sofia, Collet, Corinne
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2023
• Series: European Journal of Human Genetics
• Subjects: Birth defects; Child; Child, Preschool; Cranial sutures; Craniosynostoses - diagnosis; Craniosynostoses - genetics; Craniosynostosis; Dysostosis; Fibroblast growth factor receptor 2; Humans; Infant; Infants; Life Sciences; Pathogenicity; Medical research; Genetics research
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-023-01295-y

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.