A novel compound heterozygous mutation in ADAMTS17 identified in a Chinese family with Weill-Marchesani syndrome

AIM: To investigate the genetic basis of Weill-Marchesani syndrome (WMS) in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations. METHODS: Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings. Whole-exome sequencing (WES) was conducted for the proband and other family members. Bioinformatics tools were used to evaluate the conservation, predicted pathogenicity, and structural effects of the identified ADAMTS17 variants. In addition, protein structure modeling was applied to assess the functional impacts of the mutations. RESULTS: The proband (a 32-year-old male) and his elder sister (42y) presented typical clinical features of WMS, including short stature, brachydactyly, high myopia, ectopia lentis, and secondary glaucoma. WES identified a novel compound heterozygous mutation in ADAMTS17: a splicing mutation (c.451-2A>G) inherited from the father and a missense mutation (c.1043G>A; p.C348Y) inherited from the mother. The splicing mutation disrupted normal mRNA splicing and processing, leading to premature translation termination. The missense mutation, which is located in the metalloprotease catalytic domain, was predicted to abolish a critical disulfide bond, thereby impairing protein stability. Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms. CONCLUSION: A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family, and its pathogenicity is verified via bioinformatics analysis and protein structural modeling. These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.