Response to Brosens et al
Response to Brosens et al
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DOI：
10.1038/gim.2018.7
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发表时间：
2018-03
影响因子：
8.8
通讯作者：
Qian Jiang;Xiao Chen;Feng Zhang;A. Chakravarti;Longlei Li
中科院分区：
文献类型：
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作者：
Qian Jiang;Xiao Chen;Feng Zhang;A. Chakravarti;Longlei Li
致编辑：我们非常感谢有机会回应Brosens等人1关于我们的第二篇文章《RET体细胞突变在先天性巨结肠症中起作用吗？》一文。首先，我们感谢Brosens和他的同事指出“对来自血液或唾液的DNA进行常规基因测试不会发现这些ENCC特有的突变，也不会很容易发现低镶嵌变异体”，因为这正是为什么我们说RET体细胞突变在先天性巨结肠中被低估的原因。这也是为什么我们建议对父母血液进行深度测序(要有足够的灵敏度)，对儿童中出现的致病性DNMS[从头突变]进行深度测序，并应能够将有意义的家庭分层为大多数家庭，其复发风险为1%，少数家庭的复发风险可能至少高一个数量级。其次，我们同意作者的观点，“HSCR是一种复杂的遗传性疾病”，“HSCR中所见的缺失遗传性是许多复杂疾病的共同特征，解释它仍然具有挑战性。”我们想强调的是，我们在论文中没有讨论缺失的遗传性，即使基于扩增子的深度测序(ADS)确实揭示了我们的有害变异病例中高频(75%)RET嵌合体。在解释这些变体的性质时，我们认真考虑了我们术语的使用，并补充道：“我们发现的所有六个马赛克突变都显示出致病性的强有力证据。其中4个被预测为零等位基因，1个已被报道，1个在高度保守的位置插入一个氨基酸，未受影响的同胞中没有，以前从未被公共的国家心肺和血液研究所或Exome聚集联盟外显子组测序项目报告过。我们认为这一描述是客观的，完全符合美国医学遗传学和基因组学学院的指导方针。值得注意的是，在8例有害的RET变异体中，只有2例(家族7和8)被证明是真正的生殖系DNM携带者。在剩下的六个家庭中，父母中的四个(家庭3-6)有一些嵌合体，包括在生殖系中，因为突变的等位基因被遗传给了孩子。这简单地说，存在RET嵌合体，当存在有害等位基因时，可能并不总是被识别。此外，当表面上健康的父母可能会有多个受影响的孩子时，使用“体细胞嵌合体”这个术语并不少见。3对于家系1和家系2的患者，我们认为这些变异代表了合子后而不是生殖系起源，原因如下：
To the Editor: We appreciate this opportunity to respond to the letter “Do RET Somatic Mutations Play a Role in Hirschsprung Disease?,” by Brosens et al., 1 regarding our article 2. First, we thank Brosens and colleagues for pointing out that “routine genetic testing on DNA derived from blood or saliva would not find these ENCC-specific mutations, nor would it easily detect low mosaic variants” because this is exactly why we say RET somatic mutations are underrecognized in Hirschsprung disease. This is also why we suggest that “deep sequencing (with enough sensitivity) of parental blood for pathogenic DNMs [de novo mutations] seen in children would be highly recommended, and should enable meaningful stratification of families into a substantial majority with a o1% recurrence risk and a small minority with a recurrence risk that could be at least an order of magnitude higher.” Second, we agree with the authors that “HSCR is a complex inherited disorder” and the “missing heritability seen in HSCR is a common feature of many complex disorders, and explaining it remains challenging.” We would like to emphasize that we did not discuss missing heritability in our paper, even though amplicon-based deep sequencing (ADS) indeed revealed high-frequency (75%) RET mosaicism among our cases with deleterious variants. While explaining the property of these variants, we seriously considered the usage of our terms and added “All of the six mosaic mutations we identified showed strong evidence of pathogenicity. Four are predicted to be null alleles, one has been reported previously, and one inserts an amino acid at a highly conserved site, is absent from the unaffected sibling, and has never been reported previously by the public National Heart, Lung, and Blood Institute or Exome Aggregation Consortium exome sequencing projects.” We believe that this description is objective and completely in line with American College of Medical Genetics and Genomics guidelines. It should be noted that among the eight cases with deleterious RET variants, only two (families 7 and 8) were demonstrated to be true germ-line DNM carriers. Of the remaining six, four (families 3–6) of the parents have some mosaicism, including in the germ line because the mutant allele was transmitted to the child. This simply says that there is RET mosaicism and the deleterious allele may not always be recognized when present. Besides, it’s not uncommon to use the term “somatic mosaicism” when apparently healthy parents can potentially have multiple affected children. 3 With respect to the patients in families 1 and 2, we think the variants represent a postzygotic instead of germline origin for the following reasons: