Purpose: Enrichment of heterozygous missense and truncating SMAD6 variants was
previously reported in non-syndromic 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
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 compared to gnomAD data (P<10-7). Combined with eight additional variants, ≥20/26
were transmitted from an unaffected parent but rs1884302 genotype did not predict
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.
- digenic inheritance
- metopic synostosis
- protein instability