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SMAD6 variants in nonsyndromic craniosynostosis

European Journal of Human Genetics volume 31, pages 611–612 (2023)Cite this article

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The Original Article was published on 03 February 2023

Premature fusion of the cranial sutures (craniosynostosis) is one of the most frequent congenital craniofacial anomalies, occurring once in every 2000 births. Syndromic craniosynostoses account for ~15% of cases and demonstrate Mendelian patterns of inheritance with well-established genetic causes [1]; however, nonsyndromic CS, accounting for ~85% of cases, is genetically heterogeneous and largely unexplored. In this article by di Rocco et al., the authors describe a molecular etiology in 12.9% of nonsyndromic sagittal and metopic CS cases in a cohort of 101 patients [2]. Most notable among genetic causes, heterozygous mutations in SMAD6 were identified in 7% of cases, with neurodevelopmental testing demonstrating delayed language acquisition in affected probands. The incidence of SMAD6 mutations in nonsyndromic CS and the presence of associated adverse neurodevelopmental consequences are consistent with prior studies of SMAD6-associated CS [3,4,5,6,7].

~95% of nonsyndromic CS cases are sporadic, implying a contribution of de novo and rare transmitted variants with reduced penetrance in conferring disease risk [6]. De novo mutations in regulators of the Wnt, BMP, and FGF/ERK signaling pathways have been identified in 5% of cases with sagittal or metopic CS, with transmitted LOF mutations in these genes occurring in an addition 5% of cases [4, 5, 8]. These three pathways converge on nuclear regulators of osteoblast differentiation, and have been highlighted among the most important in regulating neural crest cell differentiation into cartilage and bone, with defects in patterning and differentiation of CNCC resulting from mutations impacting these developmental signaling pathways [9]. The affected sutures in midline CS (sagittal and metopic) are of neural crest origin; genetic disruption of these signaling pathways are believed to cause CS via aberrant cranial neural crest morphogenesis [10, 11]. Together, the findings suggest that disruption of the balance between proliferation and differentiation of neural crest derived progenitor cells is likely to underlie a fraction of CS cases, causing premature fusion of cranial sutures [1].

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  1. Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, New York, NY, USA

    Andrew T. Timberlake

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Timberlake, A.T. SMAD6 variants in nonsyndromic craniosynostosis. Eur J Hum Genet 31, 611–612 (2023). https://doi.org/10.1038/s41431-023-01317-9

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