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Abstract: TH-PO356

Confirmatory Genetic Testing Uncovers the Unexpected: A Rare Dual PKD1/PRKCSH Diagnosis in Familial Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Darwish, Tarek, Kansas City Kidney Specialists, Overland Park, Kansas, United States
  • Brossart, Katya, Natera, Inc., Austin, Texas, United States
  • Curry, Kathryn Marie, Natera, Inc., Austin, Texas, United States
  • Punj, Sumit, Natera, Inc., Austin, Texas, United States

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) have considerable genetic and phenotypic overlap and are characterized by hepatic and renal cysts. ADPKD and ADPLD show independent inheritance, and risk of progressive disease in either organ varies greatly by genotype. Molecular diagnosis can inform prognosis and clinical management. We report a rare dual diagnosis of ADPKD and ADPLD in the context of multigenerational ADPKD, and, to our knowledge, the first finding of dual PKD1/PRKCSH pathogenic variants.

Case Description

A 50-year-old woman with ADPKD and preserved renal function presented with significant abdominal distension consistent with hepatomegaly. Imaging revealed multiple renal and hepatic cysts. Family history was notable for ADPKD in the patient’s mother, maternal grandmother, and the grandmother’s siblings. The patient’s 20-year-old daughter has renal cysts but normal kidney function. Genetic testing with a 385-gene NGS panel covering multiple genes associated with cystic diseases (the RenasightTM Test) was used to determine genetic etiology. Heterozygous pathogenic variants were identified in PKD1 (c.3957_3994dup (p.Asp1332Glyfs*27), and PRKCSH (c.374_375del (p.Glu125Valfs*21)) which are associated with ADPKD and ADPLD respectively. Both variants are predicted to be truncating. Typically, truncating PKD1 variants cause severe PKD and mild-to-severe PLD. PRKCSH-associated pathogenic variants cause mild-to-severe PLD, with absent-to-mild PKD3. Family history suggests maternal inheritance of the PKD1 variant. Absence of severe hepatic features in prior generations suggests a de novo PRKCSH variant. A family history of ADPLD cannot be confirmed due to the variable expressivity and reduced penetrance of ADPLD, and limited ADPKD-ADPLD-related phenotypic data. Cascade testing is recommended.


Single-gene confirmatory genetic testing for suspected ADPKD or ADPLD can be too narrow to capture an unexpected genetic etiology. This case highlights the value of unbiased genetic testing to confirm clinically diagnosed ADPKD. The presence of PRKCSH-related PLD in a patient with known ADPKD confers greater risk of hepatic disease progression, with implications for clinical management. This result enables familial testing for ADPKD and ADPLD risk in relatives.