Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome.
Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome.
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DOI：
10.1002/humu.22819
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发表时间：
2015-09
期刊：
影响因子：
3.9
通讯作者：
Zhang, Yuehua
中科院分区：
文献类型：
--
作者：
Xu, Xiaojing;Yang, Xiaoxu;Wu, Qixi;Liu, Aijie;Yang, Xiaoling;Ye, Adam Yongxin;Huang, August Yue;Li, Jiarui;Wang, Meng;Yu, Zhe;Wang, Sheng;Zhang, Zhichao;Wu, Xiru;Wei, Liping;Zhang, Yuehua
大多数患有Drave氏综合征(DS)的儿童是由新生的SCN1A突变引起的。为了研究突变的来源，我们开发并应用了一种新的方法，将深度扩增子重测序与贝叶斯模型相结合，以提高灵敏度来检测和定量等位基因片段。在Sanger测序判断为“从头”的174个DS先证者的SCN1A突变中，我们发现15例(8.6%)为亲本嵌合体。我们确定了另外五个亲本嵌合体病例，这些病例也可以通过桑格测序检测到。20例亲本嵌合体的突变等位基因比例在1.1%~32.6%之间。13个(65%)突变来自父方，7个(35%)来自母方。12位(60%)马赛克父母没有任何癫痫症状。其突变等位基因比例显著低于有癫痫症状的嵌合体亲本(P=0.016)。我们在血液、唾液、尿液、毛囊、口腔上皮和精液中鉴定出具有不同等位基因组分的嵌合体，表明合子后突变可以影响多个体细胞和生殖细胞。我们的结果表明，更灵敏的工具来检测父母的低水平嵌合体似乎是“从头开始”的突变，将允许更好的知情遗传咨询。
The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low‐level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling.
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