Posey Jennifer E, Harel Tamar, Liu Pengfei, Rosenfeld Jill A, James Regis A, Coban Akdemir Zeynep H, Walkiewicz Magdalena, Bi Weimin, Xiao Rui, Ding Yan, Xia Fan, Beaudet Arthur L, Muzny Donna M, Gibbs Richard A, Boerwinkle Eric, Eng Christine M, Sutton V Reid, Shaw Chad A, Plon Sharon E, Yang Yaping, Lupski James R
From the Departments of Molecular and Human Genetics (J.E.P., T.H., P.L., J.A.R., Z.H.C.A., M.W., W.B., R.X., F.X., A.L.B., D.M.M., R.A.G., C.M.E., V.R.S., C.A.S., S.E.P., Y.Y., J.R.L.) and Pediatrics (S.E.P., J.R.L.), Baylor Genetics (P.L., M.W., W.B., R.X., Y.D., F.X., R.A.G., C.M.E., Y.Y.), Program in Structural and Computational Biology and Molecular Biophysics (R.A.J.), and Human Genome Sequencing Center (D.M.M., R.A.G., E.B., S.E.P., J.R.L.), Baylor College of Medicine, the Human Genetics Center, University of Texas Health Science Center (E.B.), and the Department of Pediatrics (S.E.P., J.R.L.) and Texas Children's Cancer Center (S.E.P.), Texas Children's Hospital - all in Houston.
N Engl J Med. 2017 Jan 5;376(1):21-31. doi: 10.1056/NEJMoa1516767. Epub 2016 Dec 7.
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).
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.).
全外显子测序能够深入了解观察到的临床表型与潜在基因型之间的关系。
我们对一系列连续的7374例无关患者的数据进行了回顾性分析，这些患者被转诊至一家临床诊断实验室进行全外显子测序；我们的目标是确定报告了不止一种分子诊断的患者的频率和临床特征。使用人类表型本体中的术语计算分子诊断的疾病对之间的表型相似性。
7374例患者中有2076例（28.2%）获得了分子诊断；在这些患者中，101例（4.9%）的诊断涉及两个或更多疾病位点。我们还分析了可用的亲本样本，发现新发变异占常染色体显性疾病基因中致病变异的67.8%（90例中的61例）以及X连锁疾病基因中致病变异的51.7%（29例中的15例）；在有两个单等位基因变异的患者中，44.7%（38例中的17例）的两种变异均为新发。在12例（11.9%）有多种诊断的患者中发现了因果性拷贝数变异。与具有重叠表型特征的疾病患者（30例）相比，由两种影响不同器官系统的不同孟德尔疾病导致表型的患者（50例）的表型相似性得分显著更低（中位数得分，0.21对0.36；P = 1.77×10）。
在我们的研究中，我们发现在全外显子测序有信息价值的病例中，4.9%存在多种分子诊断。我们的结果表明，结构化临床本体可用于确定同一患者中两种孟德尔疾病之间的重叠程度；这些疾病可以是不同的或重叠的。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由两个在同一途径中相互作用的蛋白质编码基因引起。（由美国国立卫生研究院以及赵廷箴和赵威凤基金会资助。）
