Abstract: SA-PO0111
Familial CKD of Unexplained Etiology: Diagnosis at a Second Look
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Jorge, Sofia C.a., Hospital de Santa Maria, Lisbon, Portugal
- Vrbacka, Alena, Univerzita Karlova, Prague, Czechia
- Pristoupilova, Anna, Univerzita Karlova, Prague, Czechia
- Rodrigues, Marcia I G, Hospital de Santa Maria, Lisbon, Portugal
- Lopes, Jose António, Hospital de Santa Maria, Lisbon, Portugal
- Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Kmoch, Stanislav, Univerzita Karlova, Prague, Czechia
- Zivna, Martina, Univerzita Karlova, Prague, Czechia
Introduction
Despite advances in molecular genetics improving the diagnostic yield in hereditary CKD, important limitations remain. A positive family history strongly suggests monogenic disease, and re-evaluation of initially negative genetic and histological findings may lead to the correct diagnosis.
Case Description
Case description: A 28- year-old melanodermic female presented with CKD stage 4A1 (KDIGO) at 28 weeks of pregnancy, with a family history of CKD of unknown etiology; her father and uncle initiated hemodialysis in their early thirties. Clinical evaluation revealed bland urinary sediment, reduced urine density, asymptomatic hyperuricemia, and kidneys with a few cysts. Renal biopsy was inconclusive, showing glomerulosclerosis and severe tubulointerstitial fibrosis. The proband started hemodialysis at 29 years due to CKD progression. Subsequently, her brother and sister also progressed to kidney failure requiring hemodialysis at 24 and 22 years of age, respectively. All affected siblings shared similar clinical features.
Methods: Extensive genetic testing was initially negative, including NGS panel for ADTKD and cystic kidney disease genes, whole exome sequencing (WES), MLPA of HNF1B, and SnapShot analysis for the MUC1 prevalent 59dupC variant. Given the strong clinical suspicion of ADTKD-MUC1, the probands’ renal biopsy and DNA samples from affected family members were sent to a clinical research laboratory.
Results: Immunohistochemical staining for MUC1 frameshift protein (MUC1fs) showed positive tubular staining in the probands’ kidney. Repeat WES analysis in all affected individuals remained negative. Long-read sequencing of the entire MUC1 VNTR using PacBio identified a 14 bases duplication in repeat “C” at position 42 (C:42_57dupGGGCTCCACCGCCCCC), detected in all affected family members, confirming ADTKD-MUC1 diagnosis. This variant leads to biosynthesis of a pathogenic MUC1fs similar to prevalent 59dupC variant.
Discussion
Negative genetic testing does not exclude hereditary CKD. In this family, an initially inconclusive renal biopsy became decisive after MUC1fs immunostaining. Subsequent long-read sequencing of the MUC1 VNTR region identified an atypical pathogenic variant and established the correct diagnosis. This case highlights the importance of repeated diagnostic evaluation and collaboration with specialized clinical research laboratories in rare kidney diseases.