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Abstract: FR-PO607

Clinical and Genetic Characterization of Patients with CUBN Variants

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Mekraksakit, Poemlarp, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Titan, Silvia, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Tran, Cheryl L., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Vairo, Filippo, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Hogan, Marie C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background

Isolated persistent proteinuria caused by CUBN variants is rare with only a few cases reported and even fewer have had phenotypic characterization with a kidney biopsy and electron microscopy.

Methods

We retrospectively reviewed all cases undergoing genetic testing in the Mayo Clinic Nephrology Genomics Clinic with CUBN variants identified and described their clinical, pathological, and molecular genetic characteristics.

Results

We identified one patient with two CUBN variants who developed subnephrotic-range proteinuria after a urinary tract infection at 4 years and 9 months of age (UPCR 1.51 mg/mg; current cystatin eGFR 97 ml/min/1.73 m2). A kidney biopsy revealed minimal change disease (MCD) and minimal mesangial hypercellularity. A exome-based panel testing detected a variant of uncertain significance (VUS) in CUBN (NM_001081.4:c.9079G>A, p.(Gly3027Arg)) which has been reported in the homozygous or compound heterozygous state in at least one affected individual (PMID: 31613795) (PM3_Supporting) and it is predicted to have a deleterious effect to the protein (PP3). Also, this variant has a 0.0402% allele frequency in population databases (PM2_Supporting). Subsequent genome-based panel (432 kidney-related genes) identified a pathogenic deep intronic CUBN variant (NM_001081.4:c.3330-439C>G) predicted to impact splicing (PP3) and result in loss of function, a known disease mechanism for CUBN-related diseases (PMID: 10080186, 15024727, 24156255). This variant has been reported in the homozygous or compound heterozygous state in at least 3 affected individuals (PMID: 10080186, 22929189) (PM3_strong), segregated with disease in one family (PMID: 10080186), and it is absent in population databases (PM2_Supporting). Treatment with RAAS blockade, resulted in partial improvement of albuminuria. B12 levels were normal. Additionally, we identified single CUBN VUSs in 8 patients with FSGS and 1 patient with MCD. Among those, 3 required renal replacement therapy and one had a pathogenic variant in the INF2 (NM_022489.4:c.641G>A, p.(Arg214His)) associated with autosomal dominant proteinuric kidney disease.

Conclusion

We confirm the rarity of CUBN related kidney disease in our nephrology practice and highlight the utility of genome sequencing to identify non-coding variants, improving genetic diagnostic yield when targeted or exome-based panels are inconclusive.