Purpose: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Additional Metadata
Keywords BMP2, digenic inheritance, metopic synostosis, protein instability, two-locus
Persistent URL dx.doi.org/10.1038/s41436-020-0817-2, hdl.handle.net/1765/127739
Journal Genetics in Medicine
Calpena, E. (Eduardo), Cuellar, A. (Araceli), Bala, K. (Krithi), Swagemakers, S.M.A, Koelling, N. (Nils), McGowan, S.J, … Wilkie, A.O.M. (2020). SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genetics in Medicine. doi:10.1038/s41436-020-0817-2