Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder. The main clinical features include short stature with a stocky build, brachydactyly, joint stiffness, and microspherophakia. The syndrome can be inherited in an autosomal dominant manner due to heterozygous pathogenic variants in FBN1, as well as in an autosomal recessive manner associated with biallelic pathogenic variants in ADAMTS10, ADAMTS17, or LTBP2. Despite differences in inheritance patterns, the clinical manifestations are consistent. Therefore, clinical diagnosis requires genetic testing of the proband to determine the genotype, confirm the diagnosis. This study collected blood samples from a child with Weill–Marchesani syndrome (WMS) and their family members from a Chinese family. Comprehensive ophthalmologic and systemic examinations were performed. Whole-exome sequencing (WES) was conducted to detect genetic variants, and bioinformatics tools were used to screen for potential pathogenic variants. Suspected variants were validated by Sanger sequencing and comprehensively evaluated in combination with clinical data. Using the keywords “ADAMTS10” and “Weill–Marchesani syndrome,” relevant cases were retrieved from databases such as PubMed, CNKI (China National Knowledge Infrastructure), and Wanfang Medical. The genotypes and clinical manifestations of reported cases were analyzed and summarized. The proband presented with clinical features including short stature, brachydactyly, and ocular abnormalities. Ocular manifestations included high myopia, microspherophakia, and glaucoma. Whole-exome sequencing revealed a homozygous frameshift duplication variant in the ADAMTS10: NM_030957.4:c.1560_1575dup; p.Ile526Valfs*51. Both phenotypically normal parents were heterozygous carriers of the same variant. According to the variant interpretation principles of the Human Gene Mutation Database (HGMD) and the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic. A review of the literature indicated that WMS associated with ADAMTS10 variants exhibits complex and heterogeneous clinical phenotypes. A novel homozygous frameshift variant of ADAMTS10is identified in a WMS family with a history of consanguineous marriage. Our study expands the range of variations associated with WMS and deepens our understanding of pathology in disease associated with ADAMTS10 variants. The online version contains supplementary material available at 10.1186/s12920-026-02308-7.

To investigate the genetic basis of Weill-Marchesani syndrome (WMS) in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations. 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. 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. 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.

Adult Refsum disease (RD) is a rare autosomal recessive peroxisomal disorder with an estimated prevalence of fewer than 1 in 1 million. The ocular manifestations result from the accumulation of phytanic acid, leading to retinitis pigmentosa, attenuated retinal vessels, bone spicule pigmentation, optic disc pallor, and macular involvement in advanced stages. To date, there has been no documented association between RD and microspherophakia, a rare lens abnormality more commonly linked to Weill-Marchesani syndrome. Microspherophakia is characterized by a small lens diameter, increased anteroposterior thickness, and a visible lens equator upon full mydriasis. We present a unique case of concurrent RD and microspherophakia.

Weill-Marchesani syndrome (WMS) is characterized by severe short stature, joint contractures, tight skin, heart valve and eye anomalies. WMS is caused by biallelic mutations in ADAMTS10, ADAMTS17, or LTBP2, or mono-allelic mutations in FBN1 Because bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected extracellular matrix (ECM) proteins contribute to chondrocyte and growth plate function. Here, we show that Adamts10;Adamts17 double knockout (DKO) mice have significant postnatal lethality and exacerbated bone shortening, which correlated with a narrower hypertrophic zone in their growth plates. Potential ADAMTS17 substrates identified by N-terminomics and yeast-2-hybrid screening revealed the ECM proteins fibronectin (FN1) and collagen VI (COL6A2). In primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts, fibronectin deposition was impaired concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages.

Weill-Marchesani syndrome (WMS) is characterized by severe short stature, short hands and feet (brachydactyly), joint contractures, tight skin, and heart valve, eye, and skin anomalies. Whereas recessive WMS is caused by mutations in ADAMTS10, ADAMTS17, or LTBP2, dominant WMS is caused by mutations in FBN1 (encoding fibrillin-1). Since bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected ECM proteins act within the same pathway to regulate chondrocyte and growth plate function. Here, we investigated the role of the secreted ADAMTS proteases ADAMTS10 and ADAMTS17 in growth plate function and ECM formation. We generated Adamts10;Adamts17 double knockout (DKO) mice, which showed significant postnatal lethality compared to single Adamts10 or Adamts17 KO mice. Importantly, we observed severe bone shortening DKO mice, which correlated with a narrower hypertrophic zone in their growth plates. ADAMTS17 substrates identified by N-terminomics and yeast two-hybrid screening identified the ECM proteins fibronectin and collagen VI (COL6). However, validation experiments did not reveal direct proteolysis of either fibronectin or COL6 by ADAMTS17. We then investigated ECM formation in primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts and observed compromised fibronectin deposition concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Collectively, our data suggest that ADAMTS10 and ADAMTS17 regulate bone growth by regulating chondrocyte hypertrophy or hypertrophic chondrocyte turnover. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages, possibly regulating the spatio-temporal deposition of fibrillin isoforms.