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A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably

Daniel R Evans1, Jane S Green1, Somayyeh Fahiminiya2,3

  • 1Discipline of Genetics, Memorial University of Newfoundland, Faculty of Medicine, St. Johns, NL, A1B 3V6, Canada.

Scientific Reports
|July 4, 2020
PubMed

Insights

Weill-Marchesani syndrome (WMS) patients with a novel ADAMTS17 variant show subtle hand abnormalities. Anthropometric analysis revealed shortened metacarpals, expanding knowledge of WMS pathogenesis and variable phenotypes.

Area of Science:

  • Genetics and Molecular Biology
  • Human Genetics
  • Biochemistry

Background:

  • Weill-Marchesani syndrome (WMS) is a rare genetic disorder characterized by short stature, brachydactyly, joint stiffness, and ocular anomalies.
  • While pathogenic variants in ADAMTS17 are known to cause WMS, the specific hand phenotype, particularly brachydactyly, can be variable and less pronounced in some cases.

Purpose of the Study:

  • To investigate the genetic basis and phenotypic spectrum of WMS in a large Canadian family.
  • To elucidate the molecular mechanism underlying the variable hand phenotype in WMS patients with ADAMTS17 variants.

Main Methods:

  • Whole exome sequencing and autozygosity mapping to identify genetic variants.
  • Sanger sequencing for variant co-segregation analysis.
  • Detailed anthropometric analysis of hand roentgenograms and in vitro cell-based assays to assess protein function.

Main Results:

  • A novel pathogenic missense ADAMTS17 variant (c.3068G>A, p.C1023Y) was identified and co-segregated with WMS in the family.
  • Affected individuals exhibited sub-clinical brachydactyly, characterized by disproportionately small metacarpophalangeal bones, with intrafamilial variability.
  • The identified ADAMTS17 variant significantly reduced protein secretion in HEK293T cells.

Conclusions:

  • This study expands the understanding of ADAMTS17's role in WMS pathogenesis, highlighting its contribution to a variable and potentially sub-clinical hand phenotype.
  • Anthropometric measurements of hand roentgenograms are valuable tools for characterizing brachydactyly in WMS.
  • The findings provide insights into the molecular mechanisms affecting protein secretion and its impact on WMS phenotypes.

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