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Abstract：
A family of five male siblings (three survivors at 48, 53 and 58 years old; two deceased at 8 months old and 2.5 years old) demonstrating significant phenotypic variability ranging from intermediate to the myosclerotic like Bethlem myopathy is presented. Whole-exome sequencing (WES) identified a new homozygous missense mutation chr21:47402679 T > C in the canonical splice donor site of the second intron (c.227 + 2T>C) in the COL6A1 gene. mRNA analysis confirmed skipping of exon 2 encoding 925 amino-acids in 94-95% of resulting transcripts. Three sibs presented with intermediate phenotype of collagen VI-related dystrophies (48, 53 and 2.5 years old) while the fourth sibling (58 years old) was classified as Bethlem myopathy with spine rigidity. The two older siblings with the moderate progressive phenotype (48 and 53 years old) lost their ability to maintain a vertical posture caused by pronounced contractures of large joints, but continued to ambulate throughout life on fully bent legs without auxiliary means of support. Immunofluorescence analysis of dermal fibroblasts demonstrated that no type VI collagen was secreted in any of the siblings\' cells, regardless of clinical manifestations severity while fibroblast proliferation and colony formation ability was decreased. The detailed genetic and long term clinical data contribute to broadening the genotypic and phenotypic spectrum of COL6A1 related disease.
摘要：
提出了一个由五个男性兄弟姐妹组成的家庭（三个幸存者分别为48岁、53岁和58岁；两个分别在8个月大和2.5岁时死亡），表现出从中度到肌硬如Bethlem肌病的显着表型变异性。全外显子组测序（WES）在COL6A1基因的第二个内含子的经典剪接供体位点（c.2272T>C）中鉴定出一个新的纯合错义突变chr21：47402679T>C。mRNA分析证实在94-95%的所得转录物中编码925个氨基酸的外显子2的跳跃。三个同胞表现为VI型胶原相关营养不良的中间表型（48、53和2.5岁），而第四个同胞（58岁）则被归类为具有脊柱僵硬的Bethlem肌病。具有中等进行性表型的两个年长的兄弟姐妹（48岁和53岁）由于大关节明显挛缩而失去了维持垂直姿势的能力，但在没有辅助支撑手段的情况下，在完全弯曲的腿上继续行走。皮肤成纤维细胞的免疫荧光分析表明，任何同胞细胞均未分泌VI型胶原，无论临床表现的严重程度，成纤维细胞增殖和集落形成能力均下降。详细的遗传和长期临床数据有助于拓宽COL6A1相关疾病的基因型和表型谱。
