A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Her...
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ftpubmed:oai:pubmedcentral.nih.gov:7331723 2023-05-15T17:22:28+02:00 A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features Evans, Daniel R. Green, Jane S. Fahiminiya, Somayyeh Majewski, Jacek Fernandez, Bridget A. Deardorff, Matthew A. Johnson, Gordon J. Whelan, James H. Hubmacher, Dirk Apte, Suneel S. Woods, Michael O. 2020-07-02 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331723/ http://www.ncbi.nlm.nih.gov/pubmed/32616716 https://doi.org/10.1038/s41598-020-66978-8 en eng Nature Publishing Group UK http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331723/ http://www.ncbi.nlm.nih.gov/pubmed/32616716 http://dx.doi.org/10.1038/s41598-020-66978-8 © 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/. CC-BY Sci Rep Article Text 2020 ftpubmed https://doi.org/10.1038/s41598-020-66978-8 2020-07-12T00:30:05Z Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients’ hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients. Text Newfoundland PubMed Central (PMC) Canada Scientific Reports 10 1 |
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Article Evans, Daniel R. Green, Jane S. Fahiminiya, Somayyeh Majewski, Jacek Fernandez, Bridget A. Deardorff, Matthew A. Johnson, Gordon J. Whelan, James H. Hubmacher, Dirk Apte, Suneel S. Woods, Michael O. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
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Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients’ hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients. |
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Text |
author |
Evans, Daniel R. Green, Jane S. Fahiminiya, Somayyeh Majewski, Jacek Fernandez, Bridget A. Deardorff, Matthew A. Johnson, Gordon J. Whelan, James H. Hubmacher, Dirk Apte, Suneel S. Woods, Michael O. |
author_facet |
Evans, Daniel R. Green, Jane S. Fahiminiya, Somayyeh Majewski, Jacek Fernandez, Bridget A. Deardorff, Matthew A. Johnson, Gordon J. Whelan, James H. Hubmacher, Dirk Apte, Suneel S. Woods, Michael O. |
author_sort |
Evans, Daniel R. |
title |
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
title_short |
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
title_full |
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
title_fullStr |
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
title_full_unstemmed |
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
title_sort |
novel pathogenic missense adamts17 variant that impairs secretion causes weill-marchesani syndrome with variably dysmorphic hand features |
publisher |
Nature Publishing Group UK |
publishDate |
2020 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331723/ http://www.ncbi.nlm.nih.gov/pubmed/32616716 https://doi.org/10.1038/s41598-020-66978-8 |
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Canada |
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Newfoundland |
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Newfoundland |
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Sci Rep |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331723/ http://www.ncbi.nlm.nih.gov/pubmed/32616716 http://dx.doi.org/10.1038/s41598-020-66978-8 |
op_rights |
© 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/. |
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CC-BY |
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https://doi.org/10.1038/s41598-020-66978-8 |
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Scientific Reports |
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