From the Departments of Medicine (E.E.G., M.M., H.M.-R., Y.L., J.Z., J.N., P.K., W.Y.L., A.M., S. Piva, B.H.K., D.C., R.R., D.B., M.D., H.S., X.M., K.M., O.B., J.R., P.C., G.B.A., A.S.B., W.A., D.J.C., R.J.C., G.K.D., M.K.R., S.M., S.S.-C., K.K., A.G.G.) and Pediatrics (N.S.U.), Division of Nephrology, the Departments of Pathology (V.S.A.), Biomedical Informatics (D.A.F., C.W.), and Urology (S.A.), the Institute for Genomic Medicine (S.K., B.C., Z.R., J.B., C.D.M., C.M.M., N.D., D.B.G., A.G.G.) and the Department of Genetics and Development (D.B.G.), Hammer Health Sciences, and the Department of Epidemiology, Mailman School of Public Health (S.M.), Columbia University, New York; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, Innovative Medicines and Early Development (IMED) Biotech Unit, Cambridge, United Kingdom (S.C.-C., S. Petrovski, C.H., J.F., R.M., A.P.); and the Department of Medical Science, Renal Unit, Uppsala University Hospital, Uppsala, Sweden (B.C.F.).
N Engl J Med. 2019 Jan 10;380(2):142-151. doi: 10.1056/NEJMoa1806891. Epub 2018 Dec 26.
BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).
背景：外显子组测序在一些临床学科中已成为一线诊断方法，但在大多数成人遗传性疾病（包括影响全球十分之一以上人口的慢性肾脏病）中，其作用尚未得到检验。
方法：我们对两个共 3315 例慢性肾脏病患者队列进行了外显子组测序和诊断分析。我们评估了诊断率，并在有详细临床数据的患者中评估了诊断和其他有医学意义的发现的临床意义。
结果：在所有患者中，3037 例（91.6%）年龄超过 21 岁，1179 例（35.6%）自我认定为非欧洲血统。我们在 3315 例患者中的 307 例（9.3%）中检测到了诊断性变异，涵盖了 66 种不同的单基因疾病。在所检测到的疾病中，有 39 种（59%）仅在单个患者中发现。诊断性变异在所有临床定义的类别中均有发现，包括先天性或囊性肾病（531 例患者中的 127 例[23.9%]）和原因不明的肾病（281 例患者中的 48 例[17.1%]）。在评估的 2187 例患者中，有 34 例（1.6%）有医学上可干预疾病的遗传发现，尽管这些发现与他们的肾病无关，但也会导致专科转诊，并为肾脏管理提供信息。
结论：在一个超过 3000 例慢性肾脏病患者的合并队列中进行外显子组测序，仅不到 10%的病例获得了遗传诊断。（由美国国立卫生研究院和其他机构资助）。
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