A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features
Abstract 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 vari...
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crspringernat:10.1038/s41598-020-66978-8 2023-05-15T17:22:30+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. Boycott, Kym Bulman, Dennis Dyment, David McKenzie, Alex Brudno, Michael Woods, Michael O. 2020 http://dx.doi.org/10.1038/s41598-020-66978-8 http://www.nature.com/articles/s41598-020-66978-8.pdf http://www.nature.com/articles/s41598-020-66978-8 en eng Springer Science and Business Media LLC https://creativecommons.org/licenses/by/4.0 https://creativecommons.org/licenses/by/4.0 CC-BY Scientific Reports volume 10, issue 1 ISSN 2045-2322 Multidisciplinary journal-article 2020 crspringernat https://doi.org/10.1038/s41598-020-66978-8 2022-01-04T15:05:33Z Abstract 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. Article in Journal/Newspaper Newfoundland Springer Nature (via Crossref) Canada Scientific Reports 10 1 |
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Open Polar |
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Springer Nature (via Crossref) |
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crspringernat |
language |
English |
topic |
Multidisciplinary |
spellingShingle |
Multidisciplinary 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. Boycott, Kym Bulman, Dennis Dyment, David McKenzie, Alex Brudno, Michael Woods, Michael O. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features |
topic_facet |
Multidisciplinary |
description |
Abstract 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. |
format |
Article in Journal/Newspaper |
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. Boycott, Kym Bulman, Dennis Dyment, David McKenzie, Alex Brudno, Michael 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. Boycott, Kym Bulman, Dennis Dyment, David McKenzie, Alex Brudno, Michael 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 |
Springer Science and Business Media LLC |
publishDate |
2020 |
url |
http://dx.doi.org/10.1038/s41598-020-66978-8 http://www.nature.com/articles/s41598-020-66978-8.pdf http://www.nature.com/articles/s41598-020-66978-8 |
geographic |
Canada |
geographic_facet |
Canada |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
Scientific Reports volume 10, issue 1 ISSN 2045-2322 |
op_rights |
https://creativecommons.org/licenses/by/4.0 https://creativecommons.org/licenses/by/4.0 |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1038/s41598-020-66978-8 |
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Scientific Reports |
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10 |
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1 |
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1766109193783214080 |