TY - JOUR
T1 - SMAD6 variants in craniosynostosis
T2 - genotype and phenotype evaluation
AU - Calpena, Eduardo
AU - Cuellar, Araceli
AU - Bala, Krithi
AU - Swagemakers, Sigrid M.A.
AU - Koelling, Nils
AU - McGowan, Simon J.
AU - Phipps, Julie M.
AU - Balasubramanian, Meena
AU - Cunningham, Michael L.
AU - Douzgou, Sofia
AU - Lattanzi, Wanda
AU - Morton, Jenny E.V.
AU - Shears, Deborah
AU - Weber, Astrid
AU - Wilson, Louise C.
AU - Lord, Helen
AU - Lester, Tracy
AU - Johnson, David
AU - Wall, Steven A.
AU - Twigg, Stephen R.F.
AU - Mathijssen, Irene M.J.
AU - Boyadjiev, Simeon A.
AU - Wilkie, Andrew O.M.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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 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 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.
AB - 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 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 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.
KW - BMP2
KW - digenic inheritance
KW - metopic synostosis
KW - protein instability
KW - two-locus
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U2 - 10.1038/s41436-020-0817-2
DO - 10.1038/s41436-020-0817-2
M3 - Article
C2 - 32499606
AN - SCOPUS:85085969243
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
ER -