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Riedhammer, K.M.* ; Braunisch, M.C.* ; Günthner, R.* ; Wagner, M. ; Hemmer, C.* ; Strom, T.M. ; Schmaderer, C.* ; Renders, L.* ; Tasic, V.* ; Gucev, Z.* ; Nushi-Stavileci, V.* ; Putnik, J.* ; Stajić, N.* ; Weidenbusch, M.* ; Uetz, B.* ; Montoya, C.* ; Strotmann, P.* ; Ponsel, S.* ; Lange-Sperandio, B.* ; Hoefele, J.*

Exome sequencing and identification of phenocopies in patients with clinically presumed hereditary nephropathies.

Am. J. Kidney Dis. 76, 460-470 (2020)
Publ. Version/Full Text DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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/steroidresistant 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Alport Syndrome (as) ; Autosomal Dominant Tubulointerstitial Kidney Disease (adtkd) ; Ciliopathy ; Clinical Phenotype ; Congenital Anomalies Of The Kidney And Urinary Tract (cakut) ; Exome ; Focal Segmental Glomerulosclerosis (fsgs) ; Genetic Diagnosis ; Hereditary Kidney Disease ; Misdiagnosis ; Next-generation Sequencing (ngs) ; Phenocopy ; Steroid-resistant Nephrotic Syndrome (srns) ; Vacterl; Kidney-disease; Medical Genetics; American-college; Mutations; Association; Variants; Database; Guidelines; Standards; Diagnosis
ISSN (print) / ISBN 0272-6386
e-ISSN 1523-6838
Journal American Journal of Kidney Diseases
Quellenangaben Volume: 76, Issue: 4, Pages: 460-470 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
Grants Baxter, USA
German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)