A Novel Missense Mutation in a Patient with PKD

Introduction: Polycystic kidney disease (PKD) is a genetic disorder that leads to the development of renal cysts and progressive chronic kidney disease. The primary genetic variants leading to PKD are PKD1 and PKD2, which encode for the protein polycystin-1. This protein is a building block for the architecture and function of the renal tubule. Disruption in the code affects the integrity of the renal parenchyma, leading to cyst formation and a decline in renal function over time. Case Description: A 41-year-old female presented for elevated serum creatinine and a significant family history of PKD in her father and son. Her father underwent nephrectomy of his native polycystic kidneys, and her son was diagnosed with PKD after a workup of microscopic hematuria. During her workup, she underwent a renal ultrasound (Figures 1a and 1b), which revealed PKD Mayo Clinic classification 1b with additional hepatic cysts. Laboratory testing showed declining renal function with an estimated glomerular filtration rate of 48 mL/min/1.73 m2. Genetic testing was performed that was absent any known pathogenic mutation. However, a variant of unknown significance was detected with a single heterozygous non-truncating variant in PKD1 c.11214C>G (p.Asn3738Lys) predicted to result in a single amino acid substitution of Asn to Lys at codon 3738 in exon 39. 5. Discussion with genetic testing laboratory director found that it would still take time to reclassify this variant as more data becomes available with a recommendation the patient's father and/or son also undergo genetic testing to better understand the clinical significance of this variant. Discussion: PKD varies in disease severity and progression due to the complex relationship between genetic variability and epigenetic factors. With a size of over 4000 amino acids, it has been observed that small changes have profound effects on the polycystin-1 function. This case highlights the identification of novel genetic variants with potential pathological effects in PKD and the importance of enhancing our understanding of the disease at a molecular level. Further studies would be necessary to evaluate the significance of this variant to the phenotypic development of PKD.