American Journal of Kidney Diseases

Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies

Published:April 28, 2020DOI:

      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.”


      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.


      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).


      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.

      Index Words

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      Linked Article

      • Phenocopies, Phenotypic Expansion, and Coincidental Diagnoses: Time to Abandon Targeted Gene Panels?
        American Journal of Kidney DiseasesVol. 76Issue 4
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          The main goal of precision medicine is to ascertain the correct diagnosis in an individual patient to deliver the most appropriate prognosis, counseling, and treatment. Accurate diagnosis is therefore the main prerequisite in precision medicine for clinical management of both Mendelian and non-Mendelian diseases. Precise diagnosis and medical management of human diseases, especially genetic ones, can be hampered by phenocopies, genetic and phenotypic heterogeneity, and coincidental co-occurrences.
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