Kidney Week

Abstract: SA-PO599

Monoallelic PKHD1 Loss-of-Function Variants Could Be a Cause of Adult Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
  October 26, 2024 | 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: Cystic

Authors

• Fujimaru, Takuya, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Takuya Fujimaru, MD, PhD

• Mori, Takayasu, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Takayasu Mori, MD, PhD

• Sekine, Akinari, Toranomon Byoin, Minato-ku, Tokyo, Japan

Akinari Sekine, MD

• Chiga, Motoko, Tokyo Ika Shika Daigaku Byoin, Bunkyo-ku, Tokyo, Japan

Motoko Chiga

• Mandai, Shintaro, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Shintaro Mandai, MD, PhD, FASN

• Kikuchi, Hiroaki, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Hiroaki Kikuchi, MD, PhD

• Mori, Yutaro, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Yutaro Mori, MD, PhD, FASN

• Hara, Yu, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Yu Hara, MD, PhD

• Fujiki, Tamami, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Tamami Fujiki, MD

• Ando, Fumiaki, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Fumiaki Ando, MD, PhD

• Susa, Koichiro, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Koichiro Susa, MD, PhD

• Iimori, Soichiro, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Soichiro Iimori, MD, PhD

• Naito, Shotaro, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Shotaro Naito, MD, PhD

• Suwabe, Tatsuya, Toranomon Byoin, Minato-ku, Tokyo, Japan

Tatsuya Suwabe, MD, MS, PhD

• Ubara, Yoshifumi, Toranomon Byoin, Minato-ku, Tokyo, Japan

Yoshifumi Ubara, MD, PhD

• Uchida, Shinichi, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Shinichi Uchida, MD, PhD

• Sohara, Eisei, Tokyo Ika Shika Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo-ku, Tokyo, Japan

Eisei Sohara, MD, PhD

Background

PKHD1 is known as a causative gene of autosomal recessive polycystic kidney disease (ARPKD). Recently, it has been suggested that heterozygous PKHD1 variants may cause autosomal dominant polycystic kidney disease (ADPKD). However, there are few reports that have investigated the clinical characteristics and genetic background of such patients. We investigated the presence of PKHD1 pathogenic variants in patients with adult polycystic kidney disease.

Methods

We performed a comprehensive genetic analysis in 236 adult polycystic kidney families using either the cystic kidney disease-associated gene panel or the chronic kidney disease-associated gene panel.

Results

In our cohort, 166 patients (70.3%) did not have polycystic kidneys in their parents. Through this analysis, 92 patients (39%) had pathogenic variants in PKD1 or PKD2 genes. Additionally, 17 patients (7.2%) had pathogenic variants in other genes (IFT140, n = 7; HNF1B, n = 3; homozygous PKHD1, n = 2; COL4A3, n = 1; MUC1, n = 1; NPHP4, n = 1; OFD1, n = 1; PRKCSH, n = 1). In 6 of 127 patients (4.7%) who did not have any apparent pathogenic variant in known causative genes, heterozygous loss-of-function (LOF) variants of PKHD1 were detected (nonsense, n = 4; frameshift, n = 1; splicing, n = 1). In the patients with heterozygous LOF variants in PKHD1, age at the time of genetic analysis ranged from 35 to 64 years, and total kidney volumes ranged from 135 to 1193 ml. Two patients had end-stage renal disease, and the remaining four had eGFR ranging from 11 to 61 ml/min/1.73m². Furthermore, two of the six patients had heterozygous truncated variants of other autosomal recessive cystic kidney disease related genes.

Conclusion

It has been suggested that heterozygous LOF variants of PKHD1 may acquire pathological phenotypes due to the coexistence of modifiers such as modifier genes.

Funding

• Government Support – Non-U.S.