Clinical case sequencing-MCDS
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MCDS is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA was subjected to whole-exome sequencing and Sanger sequencing in all available family members. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Based on these, we found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. We draw the conclusion that two novel mutations were identified in the present work, which will further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.
施密特型干骺端软骨发育不良（Metaphyseal Chondrodysplasia, Schmid Type，简称MCDS）是一种由COL10A1基因（COL10A1 gene）突变引发的常染色体显性遗传病，以身材矮小、蹒跚步态、髋内翻及长骨弯曲为典型特征。然而目前针对MCDS表现度的相关研究报道较为罕见。本研究纳入2例先证者（proband）及可获得的受累家系成员，对其开展临床与影像学检查（clinical and radiological examination）；采集所有受累家系成员的基因组DNA（genomic DNA），对其进行全外显子组测序（whole-exome sequencing）与Sanger测序（Sanger sequencing）。此外，本研究进一步构建了X型胶原α1链（type X collagen α1 chain）C端非胶原（NC1）结构域的空间结构模型。基于上述研究结果，我们发现受累家系成员的表型呈现不完全显性（incomplete dominance）特征。突变分析显示，家系1与家系2分别存在COL10A1基因的两例新发杂合错义突变（heterozygous missense mutations）：[c.1765T>A（p.苯丙氨酸589异亮氨酸）]与[c.1846A>G（p.赖氨酸616谷氨酸）]。这两个突变位点均具有高度保守性，经计算机模拟分析（in silico analysis）预测，上述突变具有致病性。进一步的蛋白建模结果表明，这两个氨基酸替换位点均位于X型胶原α1链的NC1结构域，可能会影响X型胶原α1链的三聚化（trimerization）过程以及其与细胞周基质（pericellular matrix）分子的结合。本研究最终得出结论：本次工作中发现的两例新发突变，进一步拓展了与MCDS患者相关的COL10A1基因突变谱；此外，本研究还揭示了MCDS中存在不完全显性现象。
