Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations
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DOI：
10.1158/0008-5472.can-05-1241
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Scholl, T
中科院分区：
文献类型：
--
作者：
Judkins, T;Hendrickson, BC;Scholl, T
这项工作描述了一种方法来表征遗传性乳腺癌/卵巢癌家族患者BRCA 1基因检测过程中检测到的遗传变异的临床意义。转基因小鼠和广泛的临床试验结果支持双等位基因BRCA 1突变导致胚胎致死的假设。因此，可以合理地得出结论，发现与已知有害突变反式存在的临床意义不确定的变体降低了癌症风险。该方法应用于55，630名通过全基因直接DNA测序进行临床BRCA 1筛查的患者的大型数据集。14个常见的单核苷酸多态性（SNPs）被用来分配10个以前定义的常见，复发，或典型的单倍型在99%的这些情况下。在这些患者中检测到的总共1，477个遗传变异中，排除单倍型标记SNP，877个（59%）可以明确地分配给一个或多个单倍型。在41例病例中，先前分类为临床意义不确定的变异（主要是错义变异）由于与已知有害突变的反式重合而被排除为完全渗透突变。在总共1,150名携带这41种变异的患者中，956名携带一种变异，作为报告的唯一不确定临床意义的变异。这种方法可以广泛应用于其他疾病基因，其中复合杂合突变与生命不相容或导致明显的表型。这种主要是计算的技术是有利的，因为它依赖于现有的临床数据，并可能证明在大数据集中流行的遗传变异的信息。
This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were exclude as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.