Abstract: SA-PO581
Purely Coinci-Dent-al CLCN5 Variants Identified in Two Patients With IgA Nephropathy
Session Information
- Genetic Diseases: Diagnosis
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Raible, Darbey, Natera, Inc., Austin, Texas, United States
- Punj, Sumit, Natera, Inc., Austin, Texas, United States
- Hirachan, Padam, Cenla Kidney Specialists, Alexandria, Louisiana, United States
- Lazar, Andrew, Natera, Inc., Austin, Texas, United States
Introduction
Many monogenic forms of chronic kidney disease (CKD) exhibit phenotypic variability, making clinical diagnosis challenging. An example is Dent disease 1 (DD1), caused by variants in the CLCN5 gene, which can present with low molecular weight proteinuria and variable hypercalciuria, nephrocalcinosis, nephrolithiasis, and hyperphosphaturia. While DD1 is primarily a disorder of the proximal tubules, glomerular pathology has been reported and may contribute to CKD progression. Use of broad panel-based genetic testing may improve the ability to identify monogenic disorders and/or reclassify biopsy-based diagnoses. We report two patients with biopsy-confirmed IgA nephropathy (IgAN) in whom likely pathogenic variants in CLCN5 were identified through broad-panel genetic testing of 385 CKD associated genes (the RenasightTM test).
Case Description
Patient 1: a 38-year-old Caucasian male with history of progressive CKD (eGFR 30 mL/min/1.73 m2), proteinuria, hematuria, and biopsy-proven IgAN. Family history is significant for hematuria and unspecified diabetes mellitus in the maternal grandfather. Genetic testing revealed a likely pathogenic, hemizygous, frameshift variant in exon 9 that results in a truncation of CLCN5. The genetic diagnosis of DD1 informed counseling and prompted management changes to reduce nephrolithiasis risk.
Patient 2: a 52-year-old Caucasian male with a history of persistently elevated serum creatinine (2.24 mg/dL), proteinuria, hematuria, nephrolithiasis, and biopsy-confirmed IgAN diagnosed over three decades. Genetic testing identified a likely pathogenic, hemizygous, frameshift variant in exon 8 that results in a truncation of CLCN5. The genetic diagnosis of DD1 prompted treatment changes including cessation of hydroxychloroquine and initiation of potassium citrate and an SGLT2 inhibitor.
Discussion
These cases demonstrate the clinical utility of broad renal genetic testing in patients with renal dysfunction by identifying an unexpected co-existence of DD1 with IgAN. Cases of co-occurring IgAN with type IV collagen disorders and Fabry disease have been reported, demonstrating that individuals presenting with IgAN can have a variety of monogenic forms of CKD. Further studies are needed to determine any relationship between IgAN and these monogenic conditions, or impact on disease severity or progression.