NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation
NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation
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DOI：
10.1038/gim.2011.13
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发表时间：
2012-03-01
影响因子：
8.8
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
--
作者：
Pehlivan, Davut;Hullings, Melanie;Lupski, James R.
目的：科尔内利亚德兰格综合征（CdLS）是一种多系统先天性异常疾病，以智力迟钝、肢体畸形、面部特征明显和多毛症为特征。涉及姐妹染色单体凝聚的三个基因中的突变，NIPBL，SMC 1A和SMC 3，占CdLS病例的55%。一个显着的部分CdLS病例的分子病因仍然未知。我们假设，大基因组重排的cohesin复合物亚基基因可能发挥作用的分子病因这种disorder.Methods：自定义高分辨率寡核苷酸阵列比较基因组杂交分析询问候选人cohesin基因和断点连接测序确定的基因组变异进行。在162例已知CdLS基因突变先前测序阴性的CdLS患者中，在7例受试者中观察到含有NIPBL外显子的缺失（类似于5%）。5例患者的断点序列涉及微同源介导的复制机制，如连续复制滑动和叉停滞和模板转换/微同源介导的断裂诱导的复制作为这些拷贝数变异的潜在主要贡献者。大多数缺失预测会导致单倍不足，由于杂合性功能丧失突变，这样的突变可能会导致更严重的CdLS phenotype.Conclusion：我们的研究结果表明，一个潜在的临床效用，以测试拷贝数变异涉及NIPBL时，临床诊断的CdLS情况下，突变阴性的DNA测序研究。
Purpose: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for similar to 55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder.Methods: Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed.Results: Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (similar to 5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype.Conclusion: Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies.