Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.
Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.
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DOI：
10.1002/humu.22929
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发表时间：
2016-02
期刊：
影响因子：
3.9
通讯作者：
Lupski JR
中科院分区：
文献类型：
--
作者：
Gu S;Posey JE;Yuan B;Carvalho CM;Luk HM;Erikson K;Lo IF;Leung GK;Pickering CR;Chung BH;Lupski JR
涉及四倍体的生殖系拷贝数变异(CNV)很少见，而且产生它们的机制在很大程度上是未知的。在此之前，我们曾报道过一例妊娠20周的胎儿合并手裂畸形；临床微阵列检测到两个母系遗传的三联体，分别位于17p13.3的拷贝数中性区域，涉及BHLHA9和部分YWHAE。在这里，我们描述了一个18个月大的男性兄弟姐妹的胎儿前面描述的分裂手畸形。定制高密度阵列和数字水滴聚合酶链式反应显示，拷贝数的增加实际上是母亲、胎儿和她后来出生的儿子的四倍。在外祖母中，这种四倍-正常-四倍模式被证明是从三倍-正常-三倍CNV在相同的位点上扩展而来的。我们绘制了两个断点连接，并证明了这两个断点连接都是由Alu重复元件介导的，并且在这四个个体中是相同的。我们提出了一个结合Alu介导的复制修复机制(S)和代际、染色体内非等位基因同源重组的三步法来产生该家族的四倍体。
Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal non-allelic homologous recombination to generate the quadruplications in this family.