Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders
Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders
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DOI：
10.1016/j.ajhg.2014.07.003
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发表时间：
2014-08-07
影响因子：
9.8
通讯作者：
Stankiewicz, Pawel
中科院分区：
文献类型：
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作者：
Campbell, Ian M.;Yuan, Bo;Stankiewicz, Pawel
新的人类突变被认为起源于生殖细胞，因此在兄弟姐妹中复发相同的突变非常罕见。然而，基因组技术的敏感性不断提高，已经发现了明显健康的父母体细胞组织中突变的嵌合现象。这种体细胞嵌合的父母也可能有生殖系嵌合，可能会导致意想不到的代际复发。在这里，我们表明，在患有单纯性遗传病的儿童的父母中，传播突变的体细胞镶嵌现象比目前认识到的更常见。使用个体特异性断点PCR的灵敏度，我们前瞻性地筛选了100个家庭的儿童受基因组疾病，由于罕见的缺失拷贝数变异（CNVs）确定为从头通过父母的DNA临床分析。令人惊讶的是，我们确定了4例低水平的体细胞嵌合体的传播CNV的DNA分离自父母的血液。根据我们的观察结果，配子发生的综合概率模型预测，父母血液中的突变比仅限于种系的父母突变大大增加复发风险。此外，尽管事实上，母系传播的突变是少数的等位基因，我们的模型表明，在配子发生的性二态性的结果在更大比例的体细胞嵌合体传播的母亲，从而在复发的风险增加。因此，体细胞嵌合现象加上配子发生的性别差异可能解释了相当一部分X连锁隐性遗传病的意外复发。总的来说，我们的研究结果强调了体细胞嵌合和有丝分裂复制突变机制在传递遗传学中的重要作用。
New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.