SMAD6 and craniosynostosis: The fact that eight of the 13 rare heterozygous damaging variants in SMAD6 seen in our cohort are frameshift (n = 5) or premature termination (n = 3) mutations, which are distributed throughout the encoded protein (Figure 2a), strongly supports haploinsufficiency as the mechanism of the genetic contribution of SMAD6 to craniosynostosis.