ADAMTS17 and Weill-Marchesani Syndrome

ADAMTS17 has been robustly implicated in the etiology of Weill-Marchesani syndrome, a connective tissue disorder characterized by a constellation of clinical features including short stature, ocular anomalies (such as high myopia, ectopia lentis, and glaucoma), brachydactyly, joint stiffness, and abnormal heart morphology (PMID:22486325). Multiple studies from diverse geographical regions have reported homozygous as well as compound heterozygous mutations in this gene, underscoring an autosomal recessive inheritance pattern.

Genetic evidence from case reports and multi‐patient studies has identified more than 20 probands across several unrelated families, with segregation analysis in consanguineous pedigrees further supporting the disease association (PMID:24940034, PMID:19836009). Detailed familial studies demonstrate co‐segregation of ADAMTS17 variants with the syndrome, strengthening the overall gene-disease assertion.

The variant spectrum comprises diverse mutational types including frameshift, nonsense, and splice-site mutations. For instance, the frameshift variant selected for summary, c.652del (p.Asp218ThrfsTer41), exemplifies the disruptive nature of these alterations which abrogate ADAMTS17 protein function. Such variants are recurrent across independent studies and have been observed in multiple ethnic backgrounds (PMID:31019231).

Functional assessments have provided mechanistic insights showing that mutations in ADAMTS17 lead to impaired secretion and abnormal extracellular matrix assembly. In vitro studies, alongside animal and cellular models, demonstrate that the failure in proper processing of the protein correlates with the clinical manifestations observed in patients, thereby linking the molecular defect to the phenotype (PMID:31726086, PMID:33484187).

Collectively, the convergence of genetic and functional evidence supports a strong association between ADAMTS17 mutations and Weill-Marchesani syndrome. While additional evidence is available and exceeds the ClinGen scoring maximum, the synthesized data is sufficient to inform diagnostic decision-making, support commercial genetic testing, and bolster future publication efforts.

Key take‑home: ADAMTS17 mutation screening is clinically actionable in patients with characteristic Weill-Marchesani features, enabling precise diagnosis and management.

References

• Ophthalmic genetics • 2012 • Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation PMID:22486325
• Molecular vision • 2014 • Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome PMID:24940034
• Journal of human genetics • 2019 • A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill-Marchesani syndrome from a Chinese family PMID:31019231
• Scientific reports • 2020 • A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features PMID:32616716
• American journal of human genetics • 2009 • Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature PMID:19836009
• Matrix biology • 2020 • A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix PMID:31726086
• FASEB journal • 2021 • Alternative splicing of the metalloprotease ADAMTS17 spacer regulates secretion and modulates autoproteolytic activity PMID:33484187

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