Abstract
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 nearBMP2 (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.