SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Craniosynostosis involves premature fusion of skull sutures.
• SMAD6 variants were previously linked to specific craniosynostosis types.
• The role of SMAD6 variants and BMP2 polymorphisms in craniosynostosis penetrance is unclear.

Purpose of the Study:

• Determine SMAD6 variant occurrence across all craniosynostosis types.
• Evaluate the functional impact of SMAD6 missense variants.
• Assess if the BMP2 polymorphism rs1884302 modifies craniosynostosis phenotype.

Main Methods:

• Resequencing of SMAD6 in 795 patients with unsolved craniosynostosis.
• Genotyping of rs1884302 in SMAD6-positive individuals and relatives.
• In vitro assessment of SMAD6 missense variant inhibitory activity and stability.

Main Results:

• Identified 18 rare damaging SMAD6 variants (2.3% prevalence), with 5.8% in metopic synostosis.
• Observed an 18.3-fold enrichment of loss-of-function SMAD6 variants compared to gnomAD.
• Found that rs1884302 genotype did not predict phenotype in affected families.

Conclusions:

• Pathogenic SMAD6 variants significantly increase craniosynostosis risk, especially metopic synostosis.
• Functional analysis is crucial for evaluating missense SMAD6 variants.
• rs1884302 genotyping lacks clinical utility; phenotype diversity mechanisms remain unknown.