Abstract: SA-PO0114
Variants of Uncertain Significance in ADPKD: Diagnostic and Prognostic Implications of Genetic Testing
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)
Author
- Hulwi, Hasan, Weill Cornell Medicine, New York, New York, United States
Introduction
ADPKD is most commonly caused by pathogenic variants in PKD1 and PKD2. Multigene panel testing has identified IFT140 — an intraflagellar transport gene - as well as variants of uncertain significance (VUS), introducing diagnostic, prognostic, and therapeutic challenges.
We report two patients with imaging consistent with ADPKD who underwent Natera Renasight™ multigene kidney gene panel testing. Genetic, clinical, and radiologic data were reviewed with focus on reclassification and management impact.
Case Description
Case 1: A 49-year-old woman with a family history of cystic kidney disease (mother, age 69, preserved renal function) presented with bilateral cystic nephromegaly (ultrasound 2024: right 15.2 cm, left 14.0 cm; CT 2021: dominant cyst 7.2×9.0 cm, no hepatic involvement; creatinine 0.86 mg/dL; brain MRI: no intracranial aneurysms). Panel testing revealed no pathogenic PKD1/PKD2 variants but identified a heterozygous likely pathogenic IFT140 nonsense variant (c.2500C>T; p.Arg834*; exon 20; Genome Aggregation Database frequency <0.01%). Initially classified as a carrier for autosomal recessive Short-Rib Thoracic Dysplasia 9, this variant was reclassified following evidence establishing monoallelic IFT140 loss-of-function as ADPKD-spectrum disease — large bilateral cysts, absent hepatic involvement, favorable prognosis. Tolvaptan was withheld: vasopressin type 2 receptor (V2R) antagonism has no established role in IFT140-associated disease.
Case 2: A 51-year-old woman with bilateral renal cysts (right 13.5 cm, left 13.6 cm), hypertension, and creatinine stable at 0.9 mg/dL over 9 years had a family history of PKD (father, age 85, preserved renal function). Two sequential panels were entirely negative. A third panel identified a heterozygous PKD1 VUS — insufficient for molecular diagnosis — underscoring the limited utility of uncertain genetic results in isolation
Discussion
These cases illustrate the evolving complexity of genetic interpretation in ADPKD. IFT140 demonstrates how monoallelic non-PKD1/PKD2 ciliopathy variants expand the ADPKD spectrum, with direct therapeutic impact: tolvaptan is not indicated in IFT140-associated disease. A PKD1 VUS does not establish molecular diagnosis; sequential negative panels do not exclude ADPKD. Optimal management integrates genetic results with clinical, radiographic, and longitudinal data to guide therapy, surveillance, and counseling.