Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, glaucoma and occasionally heart defects. Given these complex clinical manifestations and genetic heterogeneity, WMS patients presented misdiagnosed as high myopia or angle closure glaucoma. Here, we report ADAMTS17 mutations, a member of the extracellular matrix protease family, from a Chinese family. Patients have features that fall within the WMS spectrum. The exome (protein-coding regions of the genome) makes up ~1 % of the genome, it contains about 85% of known disease-related variants. Whole exome sequencing (WES) has been performed to identify the disease-associated genes, including one patient, his healthy sister, and his asymptomatic wife. Genome-wide homozygosity map was used to identify the disease caused locus. SNVs and INDELs were further predicted with MutationTaster, LRT, SIFT and SiPhy and compared to dbSNP150 and 1000 Genomes project. Filtered mutation was confirmed with Sanger sequencing in whole family members. The Genome-wide homozygosity map based on WES identified a total of 20 locus which were possible pathogenic. Further, a novel nonsense mutation c.1051A >T result in p.(lys351Ter) in ADAMTS17 had been identified in a candidate loci. The Sanger sequencing data has verified two consanguineous WMS patients in the family pedigree and revealed autosomal recessive (AR) inheritance pattern. The nonsense mutation in ADAMTS17 was analyzed in silico to explore its effects on protein function. We predicted the mutation produced non-function protein sequence. A novel nonsense mutation c.1051 A > T in ADAMTS17 had been identified caused autosomal recessive WMS in the Chinese family.
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The datasets collected and/or analyzed during the current study are available from the corresponding author upon reasonable request. Please contact author for data requests.
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We would like to thank all of the study participants for their commitment. This work was supported by National Natural Science Foundation of China (#31760308, #81860173).
YSH and HAY conceived designed, review and editing the study. XZ and YCZ conducted the experiments. HAY, XZ, JL, SZH, YBK, GJW and YLY collected the data, processed data analysis and interpretation of data. HAY wrote the original manuscript. YSH critically revising the article. All authors reviewed and approved the final manuscript.
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The authors declare that they have no conflict of interest.
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The current study was approved by the Institutional Review Boards of Kunming Medical University. Written informed consent was obtained from all investigated individuals prior to the study. Before enrollment, the patients or their guardians gave informed consent.
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Yi, H., Zha, X., Zhu, Y. et al. A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill–Marchesani syndrome from a Chinese family. J Hum Genet 64, 681–687 (2019). https://doi.org/10.1038/s10038-019-0608-2