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A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features.
Sci Rep. 2020 Jul 02; 10(1):10827.SR

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.

Authors+Show Affiliations

Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.Department of Human Genetics, McGill University, Montréal, QC, H3A 1B1, Canada. McGill University and Genome Québec Innovation Centre, Montréal, QC, H3A 0G1, Canada.Department of Human Genetics, McGill University, Montréal, QC, H3A 1B1, Canada. McGill University and Genome Québec Innovation Centre, Montréal, QC, H3A 0G1, Canada.Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.Division of Genetics, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, PA, 19104, USA.Care of Dr. Jane Green, Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.Memorial University of Newfoundland, Faculty of Medicine, Discipline of Surgery (Ophthalmology), St. Johns, NL, A1B 3V6, Canada.Orthopaedic Research Laboratories, Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.No affiliation info availableDiscipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada. mwoods@mun.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32616716

Citation

Evans, Daniel R., et al. "A Novel Pathogenic Missense ADAMTS17 Variant That Impairs Secretion Causes Weill-Marchesani Syndrome With Variably Dysmorphic Hand Features." Scientific Reports, vol. 10, no. 1, 2020, p. 10827.
Evans DR, Green JS, Fahiminiya S, et al. A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features. Sci Rep. 2020;10(1):10827.
Evans, D. R., Green, J. S., Fahiminiya, S., Majewski, J., Fernandez, B. A., Deardorff, M. A., Johnson, G. J., Whelan, J. H., Hubmacher, D., Apte, S. S., & Woods, M. O. (2020). A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features. Scientific Reports, 10(1), 10827. https://doi.org/10.1038/s41598-020-66978-8
Evans DR, et al. A Novel Pathogenic Missense ADAMTS17 Variant That Impairs Secretion Causes Weill-Marchesani Syndrome With Variably Dysmorphic Hand Features. Sci Rep. 2020 Jul 2;10(1):10827. PubMed PMID: 32616716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features. AU - Evans,Daniel R, AU - Green,Jane S, AU - Fahiminiya,Somayyeh, AU - Majewski,Jacek, AU - Fernandez,Bridget A, AU - Deardorff,Matthew A, AU - Johnson,Gordon J, AU - Whelan,James H, AU - Hubmacher,Dirk, AU - Apte,Suneel S, AU - ,, AU - Woods,Michael O, Y1 - 2020/07/02/ PY - 2020/01/28/received PY - 2020/05/27/accepted PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline SP - 10827 EP - 10827 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/32616716/A_novel_pathogenic_missense_ADAMTS17_variant_that_impairs_secretion_causes_Weill-Marchesani_Syndrome_with_variably_dysmorphic_hand_features L2 - http://dx.doi.org/10.1038/s41598-020-66978-8 DB - PRIME DP - Unbound Medicine ER -
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