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Abstract: TH-PO482

Beyond COL4A: Combined Renal Histopathology and Genetic Testing Reveals the Genetic Complexity of Thin Glomerular Basement Membrane Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • Riella, Cristian, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Colombo, Dan, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Taborda Ribas, Guilherme, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Stillman, Isaac Ely, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Rennke, Helmut G., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Czarnecki, Peter G., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Improved access to genetic testing is changing the diagnostic landscape of chronic kidney disease (CKD). While renal histopathology represents the current gold standard in the differential diagnosis of CKD, the incremental diagnostic yield of genetic testing remains unknown. We aim to investigate the combined diagnostic yield of histopathology and genetic testing, and we seek to identify novel correlations between genotypes and histopathologic phenotypes.


We identified 114 patients from two academic medical centers in Boston, MA, who underwent both, kidney biopsy and kidney panel genetic testing between 1/1/2020 and 5/1/2023. We assessed pathologic diagnosis and quantifiable ultrastructural phenotypes. We then analyzed corresponding genotypes for diagnostic variants and variants of uncertain significance (VUS). Variants were grouped by genes associated with CAKUT and podocytopathy (or steroid resistant nephrotic syndrome, SRNS).


Glomerular basement membrane thinning was found in 47/114 patients, representing the most common ultrastructural abnormality. We found 16 COL4A variants in 14 patients with GBM abnormalities (8 diagnostic variants, 8 VUS). The remaining patients with GBM abnormalities had variants in dominant CAKUT genes (14 variants in 12 patients) and dominant SRNS genes (15 variants in 13 patients). 4 patients had exclusively recessive SRNS variants identified. In 8 patients, GBM abnormalities did not correlate with any variant of the above categories.
12/18 patients with COL4 variants had ultrastructural evidence of segmental or diffuse podocyte foot process effacement, and 5/18 had a diagnosis of primary FSGS.


In our retrospective cohort of patients who underwent kidney biopsy and genetic testing, thin glomerular basement membranes represented the most common ultrastructural finding. In only one third of these patients, a COL4A variant was found. Variants in dominant CAKUT and SRNS genes were the next most common findings, reflecting the genetic complexity of TBMD beyond COL4A mutations, and suggesting alternative mechanisms of disease causation.
Genetic testing for COL4A variants alone would have missed the diagnosis of TBMD in 68.9% of cases, while 3.5% of test results were found to be false positive.


  • NIDDK Support