Kidney Week

Abstract: FR-PO0121

When the Genetic Test Is Negative but the Clinicopathologic Presentation Is Not

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Kumar, Daneet, New York City Health and Hospitals Metropolitan, New York, New York, United States

Daneet Kumar, MD

• Dildar, Jalal, New York City Health and Hospitals Metropolitan, New York, New York, United States

Jalal Dildar, MD

• Lee, Sunggeun, New York City Health and Hospitals Metropolitan, New York, New York, United States

Sunggeun Lee, MD

• Baumstein, Donald I., New York City Health and Hospitals Metropolitan, New York, New York, United States

Donald I. Baumstein, MD, FASN

Introduction

Persistent hematuria and proteinuria, despite a nondiagnostic workup, may conceal collagen IV–related nephropathy and be missed on initial genetic testing.

Case Description

A 50-year-old Hispanic woman with 8-year diabetes presented with proteinuria and microscopic hematuria (<10 RBC/HPF), without hypertension, hearing loss, ocular disease, nephrolithiasis, or CKD family history.
Proteinuria improved (2.2 -0.5 g/day) with ACE inhibitor and dapagliflozin, with preserved renal function.
Serologic workup was negative, including ANA, anti-dsDNA, ANCA, RF, anti-PLA2R, HBV, HCV, C3/C4, and imaging. A kidney gene panel (Natera) was initially negative in Aug. 2024.
Light microscopy showed nonspecific changes with a thin glomerular basement membrane (GBM) and foam cells, with negative immunofluorescence. Electron microscopy (EM) demonstrated segmental GBM thinning (mean 214 nm), suggestive of an Alport spectrum disorder. Given these findings, repeat genetic interpretation in Feb. 2026 identified a likely pathogenic COL4A3 mutation, confirming collagen IV nephropathy.

Discussion

An important feature in this case was the discrepancy between initial negative genetic testing and later pathological findings identified on EM. Initial genetic panels may be false negatives due to incomplete exon coverage, inability to detect deep intronic variants, technical sequencing limitations, or reclassification of variants previously labeled as variants of uncertain significance (VUS). With advances in sequencing and expanding variant databases, repeat genetic analysis and reinterpretation can establish a diagnosis in clinically suspected cases, as seen here, where a prior VUS was later reclassified as a likely pathogenic COL4A3. In this case, EM findings of GBM thinning and focal interstitial foam cells provided important clues consistent with collagen IV–related nephropathy.
Importantly, an initially negative genetic test does not exclude a genetic etiology, and repeat interpretation is warranted when clinical and pathological findings strongly suggest a genetic disorder.

GBM thinning on EM