Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases.
Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases.
复制标题
DOI：
10.1038/gim.2016.95
复制
发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Tang S
中科院分区：
文献类型：
--
作者：
Farwell Hagman KD;Shinde DN;Mroske C;Smith E;Radtke K;Shahmirzadi L;El-Khechen D;Powis Z;Chao EC;Alcaraz WA;Helbig KL;Sajan SA;Rossi M;Lu HM;Huether R;Li S;Wu S;Nuñes ME;Tang S
诊断外显子组测序(DES)现在是对患有未诊断的遗传病的个人进行的一种常见的有序测试。外显子组测序除了为特定的疾病提供诊断外，还有能力发现新的疾病候选基因。基于家族的DES包括对特征性和新的遗传病因的分析。为了在临床环境中评估疾病的候选基因，我们开发了一个系统的、基于规则的分类方案。检测发现7.7%(72/934)的DES患者有候选基因；37(4.0%)和35(3.7%)的基因分别获得了“候选”和“可疑候选”的证据分数。在72名患者中，共有71个独立候选基因被报道，其中38%(27/71)随后在同行评议的文献中得到证实。在至少12个月前报告基因的患者中，这一确证率增加到51.9%(27/52)。在此，我们为候选基因的临床报告提供了透明、全面和标准化的评分标准。这些结果表明，DES是一种完整的基因诊断工具，特别是在阐明特征性和新的候选遗传病因的分子基础方面。基因的发现也促进了对正常人类生物学和更常见疾病的理解。Genet Med 19 2,224-235。
Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease. Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema. Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of “candidate” and “suspected candidate,” respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously. Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases. Genet Med 19 2, 224–235.