Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.
复制标题
DOI：
10.1056/nejmoa1516767
复制
发表时间：
2017-01-05
期刊：
影响因子：
--
通讯作者：
Lupski JR
中科院分区：
文献类型：
--
作者：
Posey JE;Harel T;Liu P;Rosenfeld JA;James RA;Coban Akdemir ZH;Walkiewicz M;Bi W;Xiao R;Ding Y;Xia F;Beaudet AL;Muzny DM;Gibbs RA;Boerwinkle E;Eng CM;Sutton VR;Shaw CA;Plon SE;Yang Y;Lupski JR
全外显子组测序可以提供观察到的临床表型和潜在基因型之间的关系的见解。我们对7374例连续的无关患者的数据进行了回顾性分析，这些患者被转诊到临床诊断实验室进行全外显子组测序;我们的目标是确定报告了一种以上分子诊断的患者的频率和临床特征。分子诊断的疾病对之间的表型相似性是使用人类表型本体论的术语来计算的。7374例患者中有2076例（28.2%）进行了分子诊断;在这些患者中，101例（4.9%）的诊断涉及两个或多个疾病位点。我们还分析了父母样本，发现新生变异占常染色体显性遗传病基因致病性变异的67.8%（61/90），占X连锁疾病基因致病性变异的51.7%（15/29）;这两种变异在44.7%（17/38）的具有两个单等位基因变异的患者中是新生的。在12例（11.9%）多重诊断的患者中发现了因果拷贝数变异。表型相似性评分在由两种不同的孟德尔疾病（影响不同的器官系统）引起的患者（50例患者）中显著低于具有重叠表型特征的疾病患者（30例患者）（中位数评分，0.21 vs. 0.36; P = 1.77×10−7）。在我们的研究中，我们在4.9%的病例中发现了多个分子诊断，其中全外显子组测序提供了信息。我们的研究结果表明，结构化的临床本体可以用来确定两个孟德尔疾病在同一个病人之间的重叠程度，疾病可以是不同的或重叠。不同的疾病表型影响不同的器官系统，而重叠的疾病表型更可能是由两个编码蛋白质的基因在同一途径内相互作用引起的。（由美国国立卫生研究院和丁宗和魏方超基金会资助。
Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P = 1.77×10−7). In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.)