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SMAD6 variants in craniosynostosis: genotype and phenotype evaluation
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462747/ https://www.ncbi.nlm.nih.gov/pubmed/32499606 http://dx.doi.org/10.1038/s41436-020-0817-2 |
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author | Calpena, Eduardo Cuellar, Araceli Bala, Krithi Swagemakers, Sigrid M. A. Koelling, Nils McGowan, Simon J. Phipps, Julie M. Balasubramanian, Meena Cunningham, Michael L. Douzgou, Sofia Lattanzi, Wanda Morton, Jenny E. V. Shears, Deborah Weber, Astrid Wilson, Louise C. Lord, Helen Lester, Tracy Johnson, David Wall, Steven A. Twigg, Stephen R. F. Mathijssen, Irene M. J. Boardman-Pretty, Freya Boyadjiev, Simeon A. Wilkie, Andrew O. M. |
author_facet | Calpena, Eduardo Cuellar, Araceli Bala, Krithi Swagemakers, Sigrid M. A. Koelling, Nils McGowan, Simon J. Phipps, Julie M. Balasubramanian, Meena Cunningham, Michael L. Douzgou, Sofia Lattanzi, Wanda Morton, Jenny E. V. Shears, Deborah Weber, Astrid Wilson, Louise C. Lord, Helen Lester, Tracy Johnson, David Wall, Steven A. Twigg, Stephen R. F. Mathijssen, Irene M. J. Boardman-Pretty, Freya Boyadjiev, Simeon A. Wilkie, Andrew O. M. |
author_sort | Calpena, Eduardo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7462747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-74627472020-09-16 SMAD6 variants in craniosynostosis: genotype and phenotype evaluation Calpena, Eduardo Cuellar, Araceli Bala, Krithi Swagemakers, Sigrid M. A. Koelling, Nils McGowan, Simon J. Phipps, Julie M. Balasubramanian, Meena Cunningham, Michael L. Douzgou, Sofia Lattanzi, Wanda Morton, Jenny E. V. Shears, Deborah Weber, Astrid Wilson, Louise C. Lord, Helen Lester, Tracy Johnson, David Wall, Steven A. Twigg, Stephen R. F. Mathijssen, Irene M. J. Boardman-Pretty, Freya Boyadjiev, Simeon A. Wilkie, Andrew O. M. Genet Med Article 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. Nature Publishing Group US 2020-06-05 2020 /pmc/articles/PMC7462747/ /pubmed/32499606 http://dx.doi.org/10.1038/s41436-020-0817-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Calpena, Eduardo Cuellar, Araceli Bala, Krithi Swagemakers, Sigrid M. A. Koelling, Nils McGowan, Simon J. Phipps, Julie M. Balasubramanian, Meena Cunningham, Michael L. Douzgou, Sofia Lattanzi, Wanda Morton, Jenny E. V. Shears, Deborah Weber, Astrid Wilson, Louise C. Lord, Helen Lester, Tracy Johnson, David Wall, Steven A. Twigg, Stephen R. F. Mathijssen, Irene M. J. Boardman-Pretty, Freya Boyadjiev, Simeon A. Wilkie, Andrew O. M. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation |
title | SMAD6 variants in
craniosynostosis: genotype and phenotype evaluation |
title_full | SMAD6 variants in
craniosynostosis: genotype and phenotype evaluation |
title_fullStr | SMAD6 variants in
craniosynostosis: genotype and phenotype evaluation |
title_full_unstemmed | SMAD6 variants in
craniosynostosis: genotype and phenotype evaluation |
title_short | SMAD6 variants in
craniosynostosis: genotype and phenotype evaluation |
title_sort | smad6 variants in
craniosynostosis: genotype and phenotype evaluation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462747/ https://www.ncbi.nlm.nih.gov/pubmed/32499606 http://dx.doi.org/10.1038/s41436-020-0817-2 |
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