Domingo-Gallego Andrea, Pybus Marc, Bullich Gemma, Furlano Mónica, Ejarque-Vila Laia, Lorente-Grandoso Laura, Ruiz Patricia, Fraga Gloria, López González Mercedes, Piñero-Fernández Juan Alberto, Rodríguez-Peña Lidia, Llano-Rivas Isabel, Sáez Raquel, Bujons-Tur Anna, Ariceta Gema, Guirado Lluis, Torra Roser, Ars Elisabet
Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain.
Department of Nephrology, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, Medicine Department, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain.
Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. doi: 10.1093/ndt/gfab019.
Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes.
We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1.
We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients.
Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.
遗传性肾病是30岁之前出现的慢性肾脏病（CKD）的主要病因之一。由于表型高度重叠，早发性CKD的精确临床诊断较为复杂，但基因检测是一种强大的诊断工具。我们旨在制定一种基因检测策略，以最大限度地提高早发性CKD患者的诊断率，并确定主要致病基因的患病率。
我们对460例疑似单基因病因的早发性CKD患者进行了基因检测，除了针对c.428dupC MUC1进行靶向筛查外，还使用定制设计的肾病基因panel进行下一代测序。
我们实现了65%（300/460）的总体诊断率，该诊断率因临床诊断组而异：囊性肾病为77%，肾小管病为76%，常染色体显性遗传性肾小管间质性肾病为67%，肾小球病为61%，肾和尿路先天性异常为38%。在300例基因诊断患者中，77%的患者临床诊断得到确认，15%的患者在临床诊断组内确定了具体诊断，7%的病例被重新分类。在我们队列中鉴定出的64个致病基因中，7个（COL4A3、COL4A4、COL4A5、HNF1B、PKD1、PKD2和PKHD1）占基因诊断患者的66%（198/300）。
该队列中三分之二的早发性CKD患者有遗传病因。仅7个基因就导致了大多数诊断。建立基因诊断对于明确CKD的确切病因至关重要，这有助于进行准确的遗传咨询并改善患者管理。
