Korbinian M Riedhammer1, Matthias C Braunisch1, Roman Günthner1, Matias Wagner2, Clara Hemmer3, Tim M Strom4, Christoph Schmaderer5, Lutz Renders5, Velibor Tasic6, Zoran Gucev6, Valbona Nushi-Stavileci7, Jovana Putnik8, Nataša Stajić8, Marc Weidenbusch9, Barbara Uetz10, Carmen Montoya11, Peter Strotmann12, Sabine Ponsel13, Baerbel Lange-Sperandio13, Julia Hoefele14. 1. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. 2. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 3. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. 4. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 5. Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. 6. University Children's Hospital, Medical Faculty of Skopje, Macedonia. 7. Pediatric Clinic, University Clinical Center of Kosovo, Prishtina, Kosovo. 8. Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia. 9. Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany. 10. München-Klinik Schwabing, Klinikum rechts der Isar, Technical University of Munich, Children's Hospital, Pediatric Nephrology, Munich, Germany; KfH-Kindernierenzentrum, Munich, Germany. 11. KfH-Kindernierenzentrum, Munich, Germany. 12. München-Klinik Schwabing, Klinikum rechts der Isar, Technical University of Munich, Children's Hospital, Pediatric Nephrology, Munich, Germany. 13. Division of Pediatric Nephrology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany. 14. Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address: julia.hoefele@tum.de.
Abstract
RATIONALE & OBJECTIVE: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. STUDY DESIGN: Cross-sectional cohort study. SETTING & PARTICIPANTS: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other." RESULTS: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases. LIMITATIONS: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). CONCLUSIONS: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
RATIONALE & OBJECTIVE: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. STUDY DESIGN: Cross-sectional cohort study. SETTING & PARTICIPANTS: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other." RESULTS: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases. LIMITATIONS: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). CONCLUSIONS: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
Authors: Ronen Schneider; Konstantin Deutsch; Gregory J Hoeprich; Jonathan Marquez; Tobias Hermle; Daniela A Braun; Steve Seltzsam; Thomas M Kitzler; Youying Mao; Florian Buerger; Amar J Majmundar; Ana C Onuchic-Whitford; Caroline M Kolvenbach; Luca Schierbaum; Sophia Schneider; Abdul A Halawi; Makiko Nakayama; Nina Mann; Dervla M Connaughton; Verena Klämbt; Matias Wagner; Korbinian M Riedhammer; Lutz Renders; Yoshichika Katsura; Dean Thumkeo; Neveen A Soliman; Shrikant Mane; Richard P Lifton; Shirlee Shril; Mustafa K Khokha; Julia Hoefele; Bruce L Goode; Friedhelm Hildebrandt Journal: Am J Hum Genet Date: 2020-11-23 Impact factor: 11.025
Authors: Daan Viering; Karl P Schlingmann; Marguerite Hureaux; Tom Nijenhuis; Andrew Mallett; Melanie M Y Chan; André van Beek; Albertien M van Eerde; Jean-Marie Coulibaly; Marion Vallet; Stéphane Decramer; Solenne Pelletier; Günter Klaus; Martin Kömhoff; Rolf Beetz; Chirag Patel; Mohan Shenoy; Eric J Steenbergen; Glenn Anderson; Ernie M H F Bongers; Carsten Bergmann; Daan Panneman; Richard J Rodenburg; Robert Kleta; Pascal Houillier; Martin Konrad; Rosa Vargas-Poussou; Nine V A M Knoers; Detlef Bockenhauer; Jeroen H F de Baaij Journal: J Am Soc Nephrol Date: 2021-10-04 Impact factor: 10.121
Authors: Francesca Becherucci; Samuela Landini; Luigi Cirillo; Benedetta Mazzinghi; Paola Romagnani Journal: Int J Environ Res Public Health Date: 2020-11-12 Impact factor: 3.390