Two novel mutations of COL1A1 in fetal genetic skeletal dysplasia of Chinese
Two novel mutations of COL1A1 in fetal genetic skeletal dysplasia of Chinese
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DOI：
10.1002/mgg3.1105
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发表时间：
2020-01-03
影响因子：
2
通讯作者：
Wang, Chengbin
中科院分区：
文献类型：
--
作者：
Li, Ruibing;Wang, Jianan;Wang, Chengbin
背景骨骼肌疾病具有很大的基因型和表型多样性，鉴别这些疾病并提供明确的产前诊断或植入前诊断是一个相当大的挑战。本研究的目的是确定两个无关的远交汉族家庭的致病突变。方法对2例短肢胎儿进行回顾性分析。从短肢胎儿的羊水和父母的外周血中提取基因组DNA。为了鉴定致病基因，对这两个胎儿进行基于下一代的靶捕获测序，然后在无关的健康对照中进行桑格测序。通过使用桑格测序在亲本中进行候选变体的分离分析。通过SIFT、PolyPhen和Provean分析突变。结果根据两个家系的基因突变与表型的相关性，证实胎儿遗传性骨骼发育不良。进行靶向下一代测序以筛选患者中的致病突变。发现了两个新的杂合突变COL 1A 1 c.1706 G > C（p.G569A）和c.3307 G > A（p.G1103S）。结果表明，COL 1A 1新突变存在于I型胶原α链三螺旋区Gly-X-Y序列重复中的高度保守的甘氨酸残基中，这是成骨不全的原因。错义突变的存在也用桑格序列证实。通过SIFT、PolyPhen和Provean预测这两个突变是致病性的。结论COL 1A 1基因突变可能在中国人胎儿遗传性骨骼发育不良中起重要作用。外显子组测序提高了子宫内的准确诊断，然后提供适当的遗传咨询。
Background Skeletal disorders, which have great genotypic and phenotypic varieties, are a considerable challenge to differentiate these diseases and provide a definitive prenatal diagnosis or pre-implantation. The present study aims to identify the causative mutation in two unrelated outbred Han-Chinese families. Method Two short-limb fetuses were referred to our hospital. Genomic DNA was extracted from the amniotic fluid of the short-limb fetuses and from peripheral blood of their parents. To identify the causative gene, next-generation-based target capture sequencing was performed on these two fetuses, followed by Sanger Sequencing in unrelated healthy controls. Segregation analysis of the candidate variant was performed in parents by using Sanger sequencing. The mutations were analyzed by SIFT, PolyPhen and Provean. Results We found that fetal genetic skeletal dysplasia was confirmed according to the correlations between genetic mutations and phenotypes in two Chinese families. Targeted next generation sequencing was performed to screen causative mutations in patients. Two novel heterozygous mutations COL1A1 c.1706 G > C (p. G569A) and c.3307 G > A (p. G1103S) were respectively identified. The results suggested that COL1A1 novel mutations were in highly conserved glycine residues present in the Gly-X-Y sequence repeats of the triple helical region of the collagen type I alpha chain, which was responsible for Osteogenesis Imperfecta. The presence of the missense mutation was also confirmed with the Sanger sequence. These two mutations were predicted to be pathogenic by SIFT, PolyPhen and Provean. Conclusion Our findings showed that the mutations of COL1A1 may play important roles in fetal genetic skeletal dysplasia in Chinese patients. Exome sequencing enhances the accurate diagnosis in utero then provides appropriate genetic counseling.