Abstract: SA-PO580
ADPKD-Spectrum Phenotype in Carriers of IFT172 Pathogenic Variants
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
- Elbarougy, Doaa E., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Jameel, Rohail, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Yang, Hana, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Schauer, Rachel S., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Rogers, Sean, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- McDonnell, Shannon K., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Frank, Jacob A., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Ma, Jun, Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Zagorec, Nikola, INSERM, Paris, Île-de-France, France
- Audrezet, Marie-Pierre, INSERM, Paris, Île-de-France, France
- Sayer, John Andrew, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
- Cornec-Le Gall, Emilie, INSERM, Paris, Île-de-France, France
- Larson, Nicholas B., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic Research Rochester, Rochester, Minnesota, United States
Background
ADPKD is mainly due to PKD1 and PKD2 mutations. However, ~10% are genetically unresolved or due to other loci, including IFT140. Here, we link another ciliary structural protein gene, IFT172 to the ADPKD like-phenotype.
Methods
We screened ADPKD-like patients on a 356 gene panel (Mayo PKD Center) or a custom gene panel (CHU Brest). In addition, we screened the Mayo Clinic Biobank (MCBB), UK Biobank (UKBB) and Genomics England 100kG Project cohorts, for IFT172 loss of function (LoF) variants. MCBB carriers of IFT140 LoF variants were also identified for comparison.
Results
In the cystic population, we identified 6 monoallelic IFT172 probands with LoF variants and clinical and imaging data. The mean age ±SD was 54.2±20.8, and the mean eGFR 62.8±32.3. The kidney cyst count ranged from 5 to >50. Two probands (33%) had a family history of kidney cysts. In the 52,786 MCBB individuals, we identified 66 (0.13%) with IFT172 LoF variants and 83 (0.16%) with IFT140 LoF variants. Of the 38 IFT172 patients with imaging, nine (24%) had kidney and liver cysts, 18 (47%) only kidney cysts, and four (10.5%) ICD codes for kidney cysts, including three with ADPKD codes. Of the 48 IFT140 individuals with imaging, nine (18.8%) had kidney and liver cysts, 32 (67%) only kidney cysts, and nine (18.8%) ICD codes for kidney cysts, including two with ADPKD codes. The mean eGFR ±SD were similar, 72.9±22 in the IFT172 group and 70.2±20 in the IFT140 group. Figure 1 shows the number of kidney (A) or liver (B) cysts per patient in both groups; 14.3% and 2.3% of the IFT172 and 23% and 10% of the IFT140 had ≥10 kidney or liver cysts, respectively. In the UKBB, IFT172 LoF variants were associated with cystic kidney disease ICD code Q61 (burden test p-value: 0.0114). In the 100kG project, 37 IFT172 LoF alleles were identified in a rare disease cohort of probands (n=34,082); 2 probands (5.4%) had a cystic kidney phenotype.
Conclusion
IFT140 and IFT172 LoF heterozygous variants show incomplete penetrance. The IFT172 kidney phenotype in affected patients is mild PKD with large cysts and few liver cysts, similar to monoallelic IFT140.
Funding
- NIDDK Support