A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-07-02

AUTHORS

Daniel R. Evans, Jane S. Green, Somayyeh Fahiminiya, Jacek Majewski, Bridget A. Fernandez, Matthew A. Deardorff, Gordon J. Johnson, James H. Whelan, Dirk Hubmacher, Suneel S. Apte, Kym Boycott, Dennis Bulman, David Dyment, Alex McKenzie, Michael Brudno, Michael O. Woods

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. More... »

PAGES

10827

Journal

TITLE

Scientific Reports

ISSUE

1

VOLUME

10

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-020-66978-8

DOI

http://dx.doi.org/10.1038/s41598-020-66978-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1128916261

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32616716


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24 schema:description 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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31 schema:keywords ADAMTS17
32 ADAMTS17 involvement
33 ADAMTS17 variant
34 Canada
35 HEK293T cells
36 Newfoundland
37 Sanger sequencing
38 T cells
39 WMS features
40 WMS4
41 Weill-Marchesani syndrome
42 absence
43 age
44 anthropometric
45 autozygosity mapping
46 bone
47 brachydactyly
48 cells
49 control
50 core WMS features
51 deep phenotyping
52 disorders
53 dysmorphic hand
54 ectopia lentis
55 exome sequencing
56 extracellular medium
57 family
58 features
59 hand
60 hand phenotype
61 hand roentgenograms
62 impairs secretion
63 intrafamilial variability
64 involvement
65 joint stiffness
66 large family
67 lentis
68 mapping
69 measurements
70 medium
71 metacarpophalangeal bones
72 metacarpophalangeal measurements
73 microspherophakia
74 missense ADAMTS17 variant
75 molecular pathogenesis
76 novel pathogenic missense ADAMTS17 variant
77 ocular features
78 pathogenesis
79 pathogenic missense ADAMTS17 variant
80 patient's hand
81 patients
82 phenotype
83 phenotyping
84 population
85 possible sub-clinical phenotype
86 proportionate hands
87 rare disorder
88 roentgenograms
89 role
90 secretion
91 sequencing
92 sex
93 short stature
94 siblings
95 stature
96 stiffness
97 sub-clinical brachydactyly
98 sub-clinical phenotype
99 syndrome
100 transfection
101 unaffected siblings
102 understanding
103 variability
104 variable hand phenotype
105 variant ADAMTS17
106 variants
107 whole-exome sequencing
108 work
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