BackgroundCleidocranial 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.MethodsIn this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing.ResultsAll 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.ConclusionsThe 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.

中文翻译：

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与锁颅发育不良相关的 RUNX2 变异体的鉴定

背景锁骨发育不良（CCD）是一种罕见的常染色体显性遗传疾病，主要表现为锁骨发育不全或缺失、囟门闭合延迟、多发性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，但并未在所有 CCD 患者中发现。方法在本研究中，我们通过靶向高通量 DNA 测序或 Sanger 测序检测了 7 名无关 CCD 儿童的遗传变异。结果全部患者携带 RUNX2 变体，共包括三个新的致病变异（c.722_725delTGTT，p.Leu241Serfs*8；c.231_232delTG，Ala78Glyfs*82；c.909C > G，p.Tyr303*），三个报告的致病变异（c. 577C > T，p.Arg193*；c.574G > A，p.Gly192Arg；c.673 C > T，p.Arg225Trp），一种可能的致病性变异（c.668G > T，p.Gly223Val）。对变异来源的分析表明，除了两个变异（c.909C > G，p.Tyr303*；c.668G > T，p.Gly223Val）分别遗传自患有 CCD 的患者的父亲和母亲之外，所有变异都是从头发生的。进一步的生物信息学分析表明，这些变体可以通过改变 H 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，有助于未来CCD的诊断和更好的遗传咨询。Gly223Val) 分别遗传自患有 CCD 的患者的父亲和母亲。进一步的生物信息学分析表明，这些变体可以通过改变 H 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，有助于未来CCD的诊断和更好的遗传咨询。Gly223Val) 分别遗传自患有 CCD 的患者的父亲和母亲。进一步的生物信息学分析表明，这些变体可以通过改变 H 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，有助于未来CCD的诊断和更好的遗传咨询。