Department of Clinical Genomics, Ambry Genetics, 15 Argonaut Drive, Aliso Viejo, California, 92656, USA.
Genet Med. 2019 Mar;21(3):683-693. doi: 10.1038/s41436-018-0092-7. Epub 2018 Jul 28.
Gross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications.
The DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2.
DBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic.
DBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.
由于检测方法的局限性，无法推断其上下文，即它们是串联发生还是在基因组的其他位置发生重复和插入，因此，大体重复在临床解释方面存在歧义。我们调查了乳腺癌易感性基因中串联发生的大体重复的比例，旨在为其分类提供信息。
DNA 断点分析（DBA）是一种定制的、配对末端、新一代测序（NGS）方法，旨在捕获和检测 BRCA1、BRCA2、ATM、CDH1、PALB2 和 CHEK2 中大体重复的深内含子 DNA 断点。
DBA 使我们能够确定来自 147 名先证者的 44 个独特大体重复的断点。我们确定，在该队列中，114 名（78%）携带者的重复是串联发生的，而其余携带者的重复串联状态未知。在有资格重新分类的串联大体重复中，95%被升级为致病性。
DBA 是一种新颖的、高通量的基于 NGS 的方法，它可以提供大体重复的串联状态，从而为其分类提供信息。该方法表明，在所研究的基因中，大多数大体重复是串联发生的，导致致病性分类，这有助于为携带者提供必要的治疗选择。
