Identification of RUNX2 variants associated with cleidocranial dysplasia
Identification of RUNX2 variants associated with cleidocranial dysplasia
复制标题
鉴定与锁骨颅骨发育不良相关的 RUNX2 变异
DOI：
10.1186/s41065-019-0107-7
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发表时间：
2019-09-16
期刊：
影响因子：
2.7
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
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作者：
Gao, Xueren;Li, Kunxia;Yu, Yongguo
锁骨颅发育不良（CCD）是一种罕见的常染色体显性遗传病，主要表现为锁骨发育不全或缺失，囟门关闭延迟，多处牙齿异常和身材矮小。runt相关转录因子2 （RUNX2）基因变异可导致CCD，但并非在所有CCD患者中都发现。方法采用靶向高通量DNA测序或Sanger测序对7例无亲缘关系的CCD患儿进行基因变异检测。结果所有患者携带1个RUNX2变异，包括3个新的致病变异（c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*）， 3个报道的致病变异(c.577C > T, p.Arg193*; c.574G > a, p.Gly192ArgC > T, p.Arg225Trp)，一种可能的致病变异（C . 668g > T, p.Gly223Val）。变异源分析显示，除分别从患CCD的父亲和母亲遗传的两个变异（c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val）外，所有变异均为从头开始。进一步的生物信息学分析表明，这些变异可能通过改变氢键或氨基酸的数量来影响RUNX2蛋白的结构。实验结果表明，Gly223Val突变使RUNX2蛋白无法在细胞核内定量积累。结论本研究扩大了RUNX2基因的致病变异谱，有助于今后对CCD的诊断和更好的遗传咨询。
Background Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (RUNX2) gene variants can cause CCD, but are not identified in all CCD patients. Methods In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing. Results All patients carried a RUNX2 variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C > G, p.Tyr303*), three reported pathogenic variants (c.577C > T, p.Arg193*; c.574G > A, p.Gly192Arg; c.673 C > T, p.Arg225Trp), one likely pathogenic variant (c.668G > T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C > G, p.Tyr303*; c.668G > T, p.Gly223Val) inherited from the patient's father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus. Conclusions The present study expands the pathogenic variant spectrum of RUNX2 gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.