A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features
A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features
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DOI：
10.1038/s41598-020-66978-8
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发表时间：
2020-07-02
影响因子：
4.6
通讯作者：
Woods, Michael O.
中科院分区：
文献类型：
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作者：
Evans, Daniel R.;Green, Jane S.;Woods, Michael O.
Weill-Marchesani 综合征 (WMS) 是一种罕见疾病，表现为身材矮小、短指和关节僵硬，以及包括小球形晶状体和晶状体异位在内的眼部特征。短指和关节僵硬在由 ADAMTS17 致病变异引起的 WMS4 患者中较少见。在这里，我们调查了来自加拿大纽芬兰的一个使用 WMS 的大家庭。这些患者表现出 WMS 的核心特征，但其双手的比例在临床上对于短指来说是模棱两可的。全外显子组测序和自合性图谱揭示了一种新的致病性错义 ADAMTS17 变异 (c.3068G>A, p.C1023Y)。 Sanger 测序证明变异与 WMS 共分离，并且在 150 个群体匹配的对照中不存在。鉴于 ADAMTS17 的参与，我们对患者的手进行了深度表型分析。应用于手部 X 线照片的人体测量显示，与未受影响的兄弟姐妹相比，受影响患者的掌指测量值小于其年龄和性别的预期值。此外，我们发现了一种可能的亚临床表型，涉及明显缩短的掌指骨，并具有家族内变异性。将变体 ADAMTS17 转染至 HEK293T 细胞后发现，与野生型相比，向细胞外培养基的分泌显着减少。这项工作扩大了对 ADAMTS17 分子发病机制的理解，阐明了可变的手表型，并强调了人体测量学在这些患者亚临床短指特征中的作用。
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068G>A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.