Thin Glomerular Basement Membrane Phenotypes With No Identified Pathogenic COL4A3/A4/A5 Variant

Pathogenic (P) variants in COL4A3/A4/A5 genes are known to cause thin glomerular basement membrane (GBM) or Alport-related kidney disease; however, the exact diagnostic yield of genetic testing remains unknown.

In this retrospective genotype-phenotype correlation study, we screened the patient populations of 2 major US medical centers for individuals who underwent kidney biopsy, and who had documented genetic testing results on a large 385-kidney disease gene panel. We correlated GBM thickness, estimated glomerular filtration rate, proteinuria, and hematuria with genotyping results.

We identified 115 patients with coexisting histopathology and genetic testing data, of which 49 had ultrastructural abnormalities of the GBM. Among those 49 cases, 9 had a heterozygous pathogenic or likely pathogenic (P/LP) variant in one of the COL4A genes, and 9 additional patients had COL4A variants of uncertain significance (VUS). Thirty-one patients with thin GBM were COL4A3/A4/A5 wildtype. One patient with a P variant in COL4A4 had no GBM abnormalities. Three COL4A VUS were upgraded to P/LP through experimental testing. Presence of P/LP variants in COL4A genes correlated with GBM thickness, but not with other clinical parameters. Among 31 thin GBM cases with no COL4A variant, we found variants in steroid-resistant nephrotic syndrome-, congenital anomalies of the kidneys and urinary tract (CAKUT)-, and autosomal dominant tubulointerstitial kidney disease (ADTKD) genes characterized as P/LP or as "high-risk VUS." Immune-mediated glomerular injury was as frequent in biopsy specimens with thin GBM as with normal GBM.

In our study, almost two-thirds of patients with thin GBM have no variant in COL4A3/A4/A5 genes. Our data suggest that genetic testing may not obviate the need for kidney biopsy.