Autosomal Dominant Tubulointerstitial Kidney Disease—Uromodulin Misclassified as Focal Segmental Glomerulosclerosis or Hereditary Glomerular Disease

Abstract

Introduction: Focal segmental glomerulosclerosis (FSGS) is a histopathologically defined kidney lesion. FSGS can be observed with various underlying causes, including highly penetrant monogenic renal disease. We recently identified pathogenic variants of UMOD, a gene encoding the tubular protein uromodulin, in 8 families with suspected glomerular disease.Methods: To validate pathogenic variants of UMOD, we reviewed the clinical and pathology reports of members of 8 families identified to have variants of UMOD. Clinical, laboratory, and pathologic data were collected, and genetic confirmation for UMOD was performed by Sanger sequencing.Results: Biopsy-proven cases of FSGS were verified in 21% (7 of 34) of patients with UMOD variants. The UMOD variants seen in 7 families were mutations previously reported in autosomal dominant tubulointerstitial kidney disease-uromodulin (ADTKD-UMOD). For one family with 3 generations affected, we identified p.R79G in a noncanonical transcript variant of UMOD co-segregating with disease. Consistent with ADTKD, most patients in our study presented with autosomal dominant inheritance, subnephrotic range proteinuria, minimal hematuria, and renal impairment. Kidney biopsies showed histologic features of glomerular injury consistent with secondary FSGS, including focal sclerosis and partial podocyte foot process effacement. Conclusion:Our study demonstrates that with the use of standard clinical testing and kidney biopsy, clinicians were unable to make the diagnosis of ADTKD-UMOD; patients were often labeled with a clinical diagnosis of FSGS. We show that genetic testing can establish the diagnosis of ADTKD-UMOD with secondary FSGS. Genetic testing in individuals with FSGS histology should not be limited to genes that directly impair podocyte function.

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease

“…We reported the modification of diagnosis in 30% families, including 14 families from primary diagnosis of FSGS to Alport syndrome. We also demonstrated pathogenic variants in the phenocopy genes such as UMOD 21 , TTC21B 22 , or PAX2 23 associated FSGS. The genetic subtype of FSGS established collectively accounted for 10% (12/115) of the genetic causes in our cohort.…”

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS

“…The presence of FSGS-mimics/-phenocopies emphasizes that histologically diagnosed FSGS/FGGS can represent the final common track of several hereditary kidney disease entities. This is also underlined by a recently published case of a misclassification of ADTKD-UMOD as FSGS [31].…”

Genomics Integration Into Nephrology Practice

“…Variant has been reported in other individuals with the same phenotype. LP 42 PD, PI, FT, KT 19 c GN ARHGAP24 FSGS AD c.120G>A p.(Trp40∗) Het VUS Damaging VUS in AD gene related to phenotype. Variant has been reported in other individuals with the same phenotype.…”