Andrea Domingo-Gallego1,2, Marc Pybus1,2, Gemma Bullich1,3, Mónica Furlano2, Laia Ejarque-Vila1, Laura Lorente-Grandoso1, Patricia Ruiz1, Gloria Fraga4, Mercedes López González5, Juan Alberto Piñero-Fernández6, Lidia Rodríguez-Peña7, Isabel Llano-Rivas8, Raquel Sáez9, Anna Bujons-Tur10, Gema Ariceta5, Lluis Guirado2, Roser Torra2, Elisabet Ars1,2. 1. 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. 2. 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. 3. Centre Nacional d'Anàlisi Genòmica (CNAG) - Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. 4. Department of Pediatric Nephrology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 5. Department of Pediatric Nephrology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain. 6. Department of Nephrology, Pediatrics Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. 7. Department of Clinical Genetics, Pediatrics Service, Hospital Clínico Universitario Virgen de la Arrixaca, Centre for Biomedical Research on Rare Diseases (CIBERER), Murcia, Spain. 8. Department of Genetics, Hospital Universitario Cruces, Biocruces Health Research Institute, Centre for Biomedical Research on Rare Diseases (CIBERER), Barakaldo-Bizkaia, Spain. 9. Department of Genetics, Hospital Donostia, San Sebastian, Spain. 10. Department of Urology, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, Catalonia, Spain.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Javier Naranjo; Mónica Furlano; Ferran Torres; Jonathan Hernandez; Marc Pybus; Laia Ejarque; Christian Cordoba; Lluis Guirado; Elisabet Ars; Roser Torra Journal: Clin Kidney J Date: 2021-12-28
Authors: José María García-Aznar; Luis De la Higuera; Lara Besada Cerecedo; Nerea Paz Gandiaga; Ana Isabel Vega; Gema Fernández-Fresnedo; Domingo González-Lamuño Journal: J Clin Med Date: 2022-08-19 Impact factor: 4.964