SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Genomics England Research Consortium

Research output: Contribution to journalArticlepeer-review


Purpose: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported innonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed tocontribute 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, andtested independently whether rs1884302 genotype significantly modifies thephenotype. Methods: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosisand genotyped rs1884302 in SMAD6-positiveindividuals and relatives. We examined the inhibitory activity and stability ofSMAD6 missense variants. Results: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopicsynostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variantscomparedwith gnomAD data (P < 10−7). Combined with eightadditional variants, ≥20/26 were transmitted from an unaffected parent butrs1884302 genotype did not predict phenotype. Conclusion: Pathogenic SMAD6 variantssubstantially increase the risk of both nonsyndromic and syndromic presentationsof craniosynostosis, especially metopic synostosis. Functional analysis isimportant to evaluate missense variants. Genotyping of rs1884302 is notclinically useful. Mechanisms to explain the remarkable diversity of phenotypesassociated with SMAD6 variants remainobscure.

Original languageEnglish
Pages (from-to)1498-1506
Number of pages9
JournalGenetics in Medicine
Issue number9
Publication statusPublished - Sep 1 2020


  • BMP2
  • digenic inheritance
  • metopic synostosis
  • protein instability
  • two-locus

ASJC Scopus subject areas

  • Genetics(clinical)


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