Sayer, John A

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.

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Abstract BACKGROUND AND AIMS NEK8/NPHP9 encodes a protein that localizes to the primary cilium. Biallelic NEK8 variants are known to cause multiorgan developmental defects, including kidney cystic dysplasia and extensive extra-renal defects, with heterozygous carrier parents being asymptomatic [1]. This autosomal recessive inheritance is the most common inheritance mode for ciliopathies. Complementary to this, we now propose a dominant negative effect for specific heterozygous NEK8 missense variants in the kinase domain resulting in an autosomal-dominant ciliopathy. METHOD We performed genetic testing in patients from several medical centers. To explore the consequences of the identified NEK8 variants, we are performing cilia staining assays in patients' skin fibroblast and kidney cells, as well as in mIMCD3 cells overexpressing the identified variants. Furthermore, we are examining the impact of the NEK8 variants on replication stress response. RESULTS We identified three distinct heterozygous NEK8 variants in 12 families (Table 1), all leading to missense alterations in the kinase domain. Interestingly the p.Arg45Trp variant is a recurrent variant we detected in 10 unrelated families. All patients have a kidney phenotype that varies from mild focal segmental glomerulosclerosis to prenatal presentation with polycystic kidneys. Most patients have kidney failure needing kidney replacement therapy at varying ages of onset. In all patients, we thoroughly checked whether a second variant could be found. Furthermore, the large symptomatic family and de novo occurrences favor a dominant inheritance mode. Our preliminary results from functional studies show abnormal primary cilia formation in serum-starved cells as well as increased replication stress. CONCLUSION We present the first evidence for a pathogenic effect of heterozygous NEK8 variants. Remarkably our patients present with a kidney limited phenotype as compared to the multiorgan defects found in patients with biallelic variants. This reveals a new mode of inheritance for NEK8 variants and expands genotype-phenotype correlations for this gene.