A novel homozygous ADAMTS10 frameshift variant in Weill-Marchesani syndrome in a Chinese family.

backgroundWeill–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.

methodsThis 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.

resultsThe 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.

conclusionA 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.