Characteristics and genotype-phenotype correlations in ADAMTS17 mutation-related Weill-Marchesani syndrome

Weill-Marchesani syndrome (WMS) manifests as ectopia lentis (EL), microspherophakia and short stature, which is caused by ADAMTS10, LTBP2, or ADAMTS17 gene defects. This study aims to investigate the characteristics and genotype-phenotype correlations of WMS with ADAMTS17 mutations. WMS patients with ADAMTS17 variants were identified by whole-exome sequencing from 185 patients with EL. All the included patients underwent comprehensive ocular and systemic examinations. ADAMTS17 variants were reviewed from included patients, published literature, and public databases. Bioinformatics analysis, co-segregation analysis, species sequence analysis, and protein silico modeling were used to verify the pathogenic mutations. A total of six novel ADAMTS17 mutations (c.1297C > T, c.2948C > T, c.1322+2T > C, c.1716C > G, c.1630G > A, and c.1669C > T) were identified in four WMS probands in our EL cohort (4/185, 2.16%). All probands and their biological parents presented with apparent short stature compared with the standard value. In particular, one child was detected with valvular heart disease, which has not previously been reported in patients with ADAMTS17 mutations. Conserved residues were greatly affected by the substitution of amino acids caused by these six mutations. Short stature could be considered a clue for EL patients with ADAMTS17 mutations, and much more attention needs to be paid to heart disorders among these patients. This study not only reported the characteristics of ADAMTS17 mutation-related WMS but also helped to recognize the genotype-phenotype correlations in these patients.