Massard, Pierre André

Abstract Background and Aims PKD1 and PKD2 are the two major genes in autosomal dominant polycystic kidney disease (ADPKD). Up to 15% of patients with ADPKD-like phenotype are genetically unresolved (GUR) or carry variants in minor cystogenes including IFT140. Here, we describe features of an ADPKD-like phenotype linked to monoallelic predicted loss-of-function (pLoF) variants in a new candidate cystogene, IFT172. The IFT172 protein is part of the IFT-B subcomplex and plays a role in protein trafficking within primary cilia. Biallelic variants in IFT172 cause a severe ciliopathy. Method A total of ∼3200 unrelated individuals with cystic kidney disease (CyKD) underwent genetic testing employing whole-exome sequencing (WES) or massive-parallel-sequencing (MPS) gene panels in Brest, Lyon and in Rochester, MN. In addition, 185 individuals ICD coded as CyKD from Mayo Clinic Biobank (MCBB) underwent WES. Clinical and genetic data of individuals with predicted loss-of-function variants of IFT172 were collected and analyzed. Also, the Genomics England 100kG Project cohort was screened for pLoF variants in IFT172. Results In the CyKD population, 18 patients with a monoallelic pLoF variant in IFT172 were identified. In the MCBB CyKD cohort, 3 individuals had IFT172 pLoF variants. We describe the clinical presentation of these 21 affected individuals (15 males). Median age at CyKD diagnosis was 67 (range 34–88) years. Family history for CyKD was positive in 10 (48%), negative in 9 (42%) and not known in 2 (10%) individuals. Arterial hypertension was present in 9 (45%) patients, in three of them diagnosed before age of 50 years and in 6 at a later age. Hypertension status was not known in 10 of them. A majority of the patients presented with multiple bilateral cortical kidney cysts with moderate kidney enlargement or normal-sized kidneys with large, exophytic kidney cysts and were classified as Mayo Imaging Class 2A. In one patient, unilateral CyKD was present with >10 cysts. Liver cysts were present in 4 (19%) and gout in three (15%) patients. None of the three patients who underwent screening were found to have intracranial aneurysm. Median eGFR at diagnosis (N = 19) was 53 (range 29–119) ml/min/1.73 m2. Of 15 patients older than 60 y, one had CKD stage G1, 5 stage G2, 3 stage G3a, 5 stage G3b and one G4. Only one patient of African descent (APOL1 G1/G0) reached kidney failure at age of 43 y, likely due to additional contribution of uncontrolled hypertension and poorly controlled diabetes. In addition, in two patients, the IFT172 pLoF variant was identified alongside a pathogenic variant in PKD1 (p.Gln2519*) or PKD2 (c.844-1G>T). Both progressed to kidney failure at an earlier age than typically observed with PKD1 or PKD2 alone, at 29 and 52 years, respectively. Familial segregation is ongoing. Of the total of 94,799 patients recruited in “rare disease program” within 100kG Project, 51 carried monoallelic pLoF variants in IFT172 (genetic prevalence: 5.38 [0.95 CI 3.9–6.86] per 10,000). Four of them (7.8%) had CyKD. Conclusion Carriers of monoallelic pLoF variants in IFT172 are likely to develop cystic kidney disease (CyKD) that is atypical of classical ADPKD, generally associated with a favorable kidney prognosis. Nonetheless, individuals over the age of 60 may have an increased risk of progressing to CKD stage G3 or worse. Disease penetrance in IFT172 pLoF variant carriers appears to be incomplete, similar to what is observed in IFT140.