Yang, Hana

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Key Points In a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis. Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts. Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts. Background Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity. Methods This observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants. Results Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140 ), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category. Conclusions Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

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.

Key Points Automated cyst segmentation in autosomal dominant polycystic kidney disease could transform care by enabling precise monitoring of cyst progression with minimal manual effort. This technology can facilitate more consistent assessments of cyst burden across patients. Translating these segmentation models from magnetic resonance imaging to computed tomography is crucial for providing comprehensive, modality-independent evaluations. Background Total kidney and liver volumes are key image-based biomarkers to predict the severity of kidney and liver phenotype in autosomal dominant polycystic kidney disease (ADPKD). However, magnetic resonance (MR) imaging-based advanced biomarkers like total cyst number and cyst parenchyma surface area have been shown to more accurately assess cyst burden and improve the prediction of disease progression. The main aim of this study was to extend the calculation of advanced biomarkers to other imaging modalities; thus, we propose a fully automated model to segment kidney and liver cysts in computed tomography (CT) images. Methods Abdominal CTs of patients with ADPKD were gathered retrospectively between 2001 and 2018. A three-dimensional deep learning method using the nnU-Net architecture was trained to learn cyst edges-cores and the noncystic kidney/liver parenchyma. Separate segmentation models were trained for kidney cysts in contrast-enhanced CTs and liver cysts in noncontrast CTs using an active learning approach. Two experienced research fellows manually generated the reference standard segmentation, which were reviewed by an expert radiologist for accuracy. Results Two-hundred CT scans from 148 patients (mean age, 51.2±14.1 years; 48% male) were used for model training (80%) and testing (20%). In the test set, both models showed good agreement with the reference standard segmentations, similar to the agreement between two independent human readers (model versus reader: TCN kidney/liver r =0.96/0.97 and CPSA kidney r =0.98, inter-reader: TCN kidney/liver r =0.96/0.98 and CPSA kidney r =0.99). Conclusions Our study demonstrates that automated models can segment kidney and liver cysts accurately in CT scans of patients with ADPKD.

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.