Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome
Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES Syndrome
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DOI：
10.1016/j.ajhg.2012.05.006
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发表时间：
2012-06-08
影响因子：
9.8
通讯作者：
Warman, Matthew L.
中科院分区：
文献类型：
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作者：
Kurek, Kyle C.;Luks, Valerie L.;Warman, Matthew L.
伴有血管、表皮和骨骼异常的先天性脂肪瘤过度生长 (CLOVES) 是一种偶发性非遗传性疾病，其特征是不对称躯体肥大和多个器官异常。我们假设丁香综合征是由早期胚胎发育过程中出现的体细胞突变引起的。因此，我们采用大规模并行测序在六个受影响个体的新鲜、冷冻或固定档案组织中寻找体细胞嵌合突变。我们在所有六个个体中均发现了 PIK3CA 突变，并且多个胚胎谱系受影响组织中的突变等位基因频率范围为 3% 至 30%。有趣的是，这些相同的突变已在癌细胞中被发现，它们增加了磷酸肌醇 3 激酶的活性。我们得出结论，CLOVES 是由 PIK3CA 合子后激活突变引起的。应用类似的测序策略可能会识别出偶发性非遗传性畸形的其他遗传原因。
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.