Clinical case sequencing-MCDS

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.MCDS是一种由COL10A1基因突变导致的常染色体显性遗传病，临床表型以身材矮小、蹒跚步态、髋内翻及长骨弯曲为主要特征。目前针对MCDS表现度的相关研究报道较为匮乏。本研究纳入2例先证者及受累家系成员，对其开展临床与影像学评估；提取所有可及家系成员的基因组DNA，进行全外显子组测序与桑格测序（Sanger sequencing）；同时构建X型胶原（α1）C端非胶原（NC1）结构域的空间三维模型。研究结果显示，受累家系成员的表型呈现不完全显性遗传特征。突变分析表明，家系1与家系2的COL10A1基因中分别存在2个新型杂合错义突变：[c.1765T>A (p.Phe589Ile)]与[c.1846A>G (p.Lys616Glu)]。这两个新型氨基酸替换位点具有高度保守性，经计算机模拟（in silico）分析预测为致病性突变。蛋白建模结果进一步显示，这两个突变位点均位于X型胶原（α1）的NC1结构域，可能干扰X型胶原（α1）的三聚化过程及其与细胞周基质分子的相互作用。本研究共鉴定出2个COL10A1基因新型突变，将进一步扩充MCDS相关的COL10A1基因突变谱；此外，本研究还揭示了MCDS中存在不完全显性的遗传现象。