Abstract: SA-PO0589
Monoallelic PKHD1 Loss-of-Function Variants in Adult Sporadic PKD: Potential Digenic Mechanism
Session Information
- Cystic Kidney Diseases: Clinical Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Fujimaru, Takuya, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Mori, Takayasu, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Sekine, Akinari, Toranomon Byoin, Minato, Tokyo, Japan
- Chiga, Motoko, Tokyo Kagaku Daigaku Byoin, Bunkyo, Tokyo, Japan
- Mandai, Shintaro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Kikuchi, Hiroaki, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Mori, Yutaro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Fujiki, Tamami, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Arai, Yohei, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Ando, Fumiaki, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Susa, Koichiro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Iimori, Soichiro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Naito, Shotaro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Suwabe, Tatsuya, Toranomon Byoin, Minato, Tokyo, Japan
- Ubara, Yoshifumi, Toranomon Byoin, Minato, Tokyo, Japan
- Uchida, Shinichi, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
- Sohara, Eisei, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan
Background
PKHD1 is a causative gene for autosomal recessive polycystic kidney disease (ARPKD). Recently, heterozygous PKHD1 variants have been implicated in autosomal dominant polycystic kidney disease (ADPKD), but the pathogenic mechanism remains unclear.
Methods
We performed comprehensive genetic analysis in 171 adult patients with sporadic polycystic kidney disease (PKD), defined as >5 bilateral renal cysts and no parental PKD history. Targeted next-generation sequencing was performed using panels of 69–121 genes associated with cystic or chronic kidney disease.
Results
Pathogenic variants were found in 75 patients (43.9%): PKD1 (n = 39), PKD2 (n = 18), and monoallelic IFT140 (n = 7). Eleven others had variants in genes such as HNF1B, UMOD, and OFD1. Among the 96 patients without identifiable pathogenic variants in known ADPKD genes, three (1.8%) carried heterozygous PKHD1 loss-of-function variants—two nonsense, one splicing. Two of the three also carried heterozygous variants in other autosomal recessive cystic kidney disease–related genes. Their clinical profiles at the time of genetic analysis were as follows:
- Patient 1: 35-year-old male, PKHD1:p.R1040X, plus a NPHP3 missense variant of uncertain significance; total kidney volume (TKV) 703 mL; end-stage kidney disease.
- Patient 2: 43-year-old female, PKHD1 splice-site variant plus likely pathogenic indel in TCTN1; TKV 334 mL; estimated glomerular filtration rate (eGFR) 60.5 mL/min/1.73 m2.
- Patient 3: 59-year-old male, PKHD1:p.W4X; TKV 1193 mL; eGFR 11.3 mL/min/1.73 m2.
Family testing revealed that the PKHD1 variant identified in Patient 1 was inherited from his unaffected mother, while the NPHP3 variant was not detected in her.
Conclusion
Heterozygous PKHD1 loss-of-function variants may contribute to adult-onset cystic kidney disease, particularly when accompanied by additional variants in ciliopathy-related genes. These findings support a potential modifier gene effect or digenic mechanism rather than monogenic causality.
Funding
- Government Support – Non-U.S.