Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd., Shanghai, 200233, People's Republic of China.
BMC Med Genet. 2019 Dec 19;20(1):200. doi: 10.1186/s12881-019-0937-1.
Schmid-type metaphyseal chondrodysplasia (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 of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed.
We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > 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.
Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.
Schmid 型干骺端软骨发育不良（MCDS）是一种常染色体显性遗传病，由 COL10A1 基因突变引起，其特征为身材矮小、鸭步、髋内翻和长骨弯曲。然而，MCDS 的表现度描述较为罕见。
对 2 名 MCDS 先证者及其可及的受累家系成员进行临床和影像学检查。对所有受累个体的基因组 DNA 进行全外显子组测序，在所有可及的家系成员和 250 名健康对照中通过 Sanger 测序验证候选突变。进一步构建了 X 型胶原（α1）C 端非胶原（NC1）结构域的空间模型。
我们发现，受累家系成员的表型呈现不完全外显。突变分析表明，家系 1 和 2 中 COL10A1 基因分别存在两个新的杂合错义突变[c.1765T> A（p.Phe589Ile）]和[c.1846A>G（p.Lys616Glu）]。这两个新的替代位点高度保守，通过计算机分析预测这些突变具有致病变异。此外，蛋白质建模表明，这两个取代位于 X 型胶原（α1）的 NC1 结构域，可能影响 X 型胶原（α1）的三聚体化以及与细胞外基质分子的结合。
本研究鉴定出 2 个新的突变，有助于 MCDS 的诊断，并进一步扩展与 MCDS 患者相关的 COL10A1 基因突变谱。此外，我们的研究揭示了 MCDS 中不完全外显的现象。
