INTRODUCTION: Although 10% of adults with chronic kidney disease (CKD) have a monogenic cause, the characteristics of monogenic CKD in older adults (aged ≥ 60 years) are less characterized. We aimed to assess the clinical and genetic spectrum of older adults with CKD and the clinical utility of genetic findings. METHODS: The diagnostic yield of clinically validated disease-causing variants and their type ("typical" vs. "later-onset" phenotypes) were analyzed in older patients with suspected monogenic CKD who were referred to an Irish registry according to predetermined criteria. Independent genetic diagnosis and kidney survival time predictors were analyzed using marginal logistic and Cox regression analyses. RESULTS: Two hundred sixty-five adults (from 202 families) were aged ≥ 60 years at the time of genetic testing, of which 74.3% (197/265) progressed to kidney failure. Diagnostic variants were found in 60.4% (122/202) families, including 39% of noncystic kidney disease families. Variants causing "later-onset" phenotypes were more prevalent in patients with disease-onset ≥ 60 years (56% vs. 8.3%; P ≤ 0.001), which include genetic variants in: IFT140, ALG5, ALG9, DNAJB11, COL4A5 in females, monoallelic COL4A3, and the UMOD p.Thr62Pro variant, associated with delayed onset of kidney failure compared with "typical" variants (hazard ratio: 0.52; 95% confidence interval: 0.27-0.98; P = 0.043). A family history of CKD and a priori cystic kidney disease diagnosis independently predicted genetic diagnosis (P ≤ 0.05). In 24% of older adults with positive results, the treatment plan was modified. CONCLUSION: In older patients with CKD, genetic testing revealed enriched variants associated with less-penetrant phenotypes, often with a family history of CKD, which affects clinical management.

• Keywords
• CKD, MPS, monogenic, older, polycystic kidney disease,
• Publication type
• Journal Article MeSH

BACKGROUND: MUC1 and UMOD pathogenic variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD). MUC1 is expressed in kidney, nasal mucosa and respiratory tract, while UMOD is expressed only in kidney. Due to haplo-insufficiency ADTKD-MUC1 patients produce approximately 50% of normal mucin-1. METHODS: To determine whether decreased mucin-1 production was associated with an increased COVID-19 risk, we sent a survey to members of an ADTKD registry in September 2021, after the initial, severe wave of COVID-19. We linked results to previously obtained ADTKD genotype and plasma CA15-3 (mucin-1) levels and created a longitudinal registry of COVID-19 related deaths. RESULTS: Surveys were emailed to 637 individuals, with responses from 89 ADTKD-MUC1 and 132 ADTKD-UMOD individuals. 19/83 (23%) ADTKD-MUC1 survey respondents reported a prior COVID-19 infection vs. 14/125 (11%) ADTKD-UMOD respondents (odds ratio (OR) 2.35 (95%CI 1.60-3.11, P = 0.0260). Including additional familial cases reported from survey respondents, 10/41 (24%) ADTKD-MUC1 individuals died of COVID-19 vs. 1/30 (3%) with ADTKD-UMOD, with OR 9.21 (95%CI 1.22-69.32), P = 0.03. The mean plasma mucin-1 level prior to infection in 14 infected and 27 uninfected ADTKD-MUC1 individuals was 7.06 ± 4.12 vs. 10.21 ± 4.02 U/mL (P = 0.035). Over three years duration, our longitudinal registry identified 19 COVID-19 deaths in 360 ADTKD-MUC1 individuals (5%) vs. 3 deaths in 478 ADTKD-UMOD individuals (0.6%) (P = 0.0007). Multivariate logistic regression revealed the following odds ratios (95% confidence interval) for COVID-19 deaths: ADTKD-MUC1 8.4 (2.9-29.5), kidney transplant 5.5 (1.6-9.1), body mass index (kg/m2) 1.1 (1.0-1.2), age (y) 1.04 (1.0-1.1). CONCLUSIONS: Individuals with ADTKD-MUC1 are at an eight-fold increased risk of COVID-19 mortality vs. ADTKD-UMOD individuals. Haplo-insufficient production of mucin-1 may be responsible.

• Keywords
• Autosomal Dominant Tubulointerstitial kidney disease, CA15-3, COVID-19, MUC1, Mucin-1, UMOD,
• MeSH
• COVID-19 * mortality   genetics   MeSH
• Adult MeSH
• Nephritis, Interstitial genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-1 * blood   MeSH
• Mutation * MeSH
• Registries MeSH
• SARS-CoV-2 genetics   MeSH
• Aged MeSH
• Uromodulin MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• MUC1 protein, human MeSH Browser
• Mucin-1 * MeSH
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

INTRODUCTION: Monoallelic variants in the ALG5 gene encoding asparagine-linked glycosylation protein 5 homolog (ALG5) have been recently shown to disrupt polycystin-1 (PC1) maturation and trafficking via underglycosylation, causing an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype and interstitial fibrosis. In this report, we present clinical, genetic, histopathologic, and protein structure and functional correlates of a new ALG5 variant, p.R79W, that we identified in 2 distant genetically related Irish families displaying an atypical late-onset ADPKD phenotype combined with tubulointerstitial damage. METHODS: Whole exome and targeted sequencing were used for segregation analysis of available relatives. This was followed by immunohistochemistry examinations of kidney biopsies, and targeted (UMOD, MUC1) and untargeted plasma proteome and N-glycomic studies. RESULTS: We identified a monoallelic ALG5 variant [GRCh37 (NM_013338.5): g.37569565G>A, c.235C>T; p.R79W] that cosegregates in 23 individuals, of whom 18 were clinically affected. We detected abnormal localization of ALG5 in the Golgi apparatus of renal tubular cells in patients' kidney specimens. Further, we detected the pathological accumulation of uromodulin, an N-glycosylated glycosylphosphatidylinositol (GPI)-anchored protein, in the endoplasmic reticulum (ER), but not mucin-1, an O- and N-glycosylated protein. Biochemical investigation revealed decreased plasma and urinary uromodulin levels in clinically affected individuals. Proteomic and glycoproteomic profiling revealed the dysregulation of chronic kidney disease (CKD)-associated proteins. CONCLUSION: ALG5 dysfunction adversely affects maturation and trafficking of N-glycosylated and GPI anchored protein uromodulin, leading to structural and functional changes in the kidney. Our findings confirm ALG5 as a cause of late-onset ADPKD and provide additional insight into the molecular mechanisms of ADPKD-ALG5.

• Keywords
• ALG5, Golgi apparatus, N-Linked protein glycosylation, UMOD, autosomal dominant tubulo-interstitial kidney disease, autosomal-dominant polycystic kidney disease,
• Publication type
• Journal Article MeSH

INTRODUCTION: Patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) usually present with nonspecific progressive chronic kidney disease (CKD) with mild to negative proteinuria and a family history. ADTKD-MUC1 leads to the formation of a frameshift protein that accumulates in the cytoplasm, leading to tubulointerstitial damage. ADTKD-MUC1 prevalence remains unclear because MUC1 variants are not routinely detected by standard next-generation sequencing (NGS) techniques. METHODS: We developed a bioinformatic counting script that can detect specific genetic sequences and count the number of occurrences. We used DNA samples from 27 patients for validation, 11 of them were patients from the Lille University Hospital in France and 16 were from the Wake Forest Hospital, NC. All patients from Lille were tested with an NGS gene panel with our script and all patients from Wake Forest Hospital were tested with the snapshot reference technique. Between January 2018 and February 2023, we collected data on all patients diagnosed with MUC1 variants with this script. RESULTS: A total of 27 samples were tested anonymously by the BROAD Institute reference technique for confirmation and we were able to get a 100% concordance for MUC1 diagnosis. Clinico-biologic characteristics in our cohort were similar to those previously described in ADTKD-MUC1. CONCLUSION: We describe a new simple and cost-effective method for molecular testing of ADTKD-MUC1. Genetic analyses in our cohort suggest that MUC1 might be the first cause of ADTKD. Increasing the availability of MUC1 diagnosis tools will contribute to a better understanding of the disease and to the development of specific treatments.

• Keywords
• ADTKD, MUC1, VNTR,
• Publication type
• Journal Article MeSH

INTRODUCTION: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of chronic kidney disease. ADTKD pregnancy outcomes have not previously been described. METHODS: A cross-sectional survey was sent to women from ADTKD families. RESULTS: Information was obtained from 85 afffected women (164 term pregnancies) and 23 controls (50 pregnancies). Only 16.5% of genetically affected women knew they had ADTKD during pregnancy. Eighteen percent of ADTKD mothers had hypertension during pregnancy versus 12% in controls (p = 0.54) and >40% in comparative studies of chronic kidney disease in pregnancy. Eleven percent of births of ADTKD mothers were <37 weeks versus 0 in controls (p < 0.0001). Cesarean section occurred in 19% of pregnancies in affected women versus 38% of unaffected individuals (p = 0.06). Only 12% of babies required a neonatal intensive care unit stay. CONCLUSIONS: ADTKD pregnancies had lower rates of hypertension during pregnancy versus other forms of chronic kidney disease, which may have contributed to good maternal and fetal outcomes.

• Keywords
• MUC1, Maternal health, UMOD, autosomal dominant tubulointerstitial kidney disease, epidemiology, pregnancy,
• Publication type
• Journal Article MeSH

The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.

• Keywords
• Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1, REN, UMOD,
• MeSH
• Renal Insufficiency, Chronic * MeSH
• Adult MeSH
• Genetic Testing * MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation MeSH
• Aged MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Uromodulin MeSH

BACKGROUND AND AIMS: Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. METHODS: In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. RESULTS: Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P < 0.001) of a positive genetic diagnosis. CONCLUSIONS: A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients.

• Keywords
• Chronic kidney disease, Genetic kidney disease, Inherited kidney diseases, Next-generation sequencing, Polycystic kidney genetics,
• MeSH
• Renal Insufficiency, Chronic * diagnosis   epidemiology   genetics   MeSH
• Adult MeSH
• Genetic Testing methods   MeSH
• TRPP Cation Channels genetics   MeSH
• Kidney MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation MeSH
• Polycystic Kidney, Autosomal Dominant * diagnosis   MeSH
• Prospective Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• TRPP Cation Channels MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of disorders with a bland urinary sediment, slowly progressive chronic kidney disease (CKD), and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD in both children and adults. ADTKD-REN presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-UMOD is associated with gout and CKD that may present in adolescence and slowly progresses to kidney failure. HNF1β mutations often present in childhood with anatomic abnormalities such as multicystic or dysplastic kidneys, as well as CKD and a number of other extra-kidney manifestations. ADTKD-MUC1 is less common in childhood, and progressive CKD is its sole clinical manifestation, usually beginning in the late teenage years. This review describes the pathophysiology, genetics, clinical characteristics, diagnosis, and treatment of the different forms of ADTKD, with an emphasis on diagnosis. We also present data on kidney function in children with ADTKD from the Wake Forest Rare Inherited Kidney Disease Registry.

• Keywords
• Autosomal dominant, Chronic kidney disease, HNF1β, Inherited, Mucin-1, Pediatric, Renin, Uromodulin,
• MeSH
• Renal Insufficiency, Chronic * MeSH
• Child MeSH
• Gout * MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• Polycystic Kidney Diseases * MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Uromodulin MeSH

INTRODUCTION: Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1. METHODS: This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals. RESULTS: Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were <5 U/mL in 22% of ADTKD-MUC1 patients, in 0/249 controls, and in 1% of the reference population. Plasma CA15-3 levels were >20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate. DISCUSSION/CONCLUSIONS: Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.

• Keywords
• ADTKD-MUC1, Autosomal dominant tubulointerstitial kidney disease, CA15-3, Mucin-1, rs4072037,
• MeSH
• Alleles MeSH
• Biomarkers blood   MeSH
• Adult MeSH
• Nephritis, Interstitial blood   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-1 blood   genetics   MeSH
• Mutation MeSH
• Prognosis MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Uromodulin genetics   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Biomarkers MeSH
• MUC1 protein, human MeSH Browser
• Mucin-1 MeSH
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

• Keywords
• ADTKD, HNF-1B, MUC-1, UMOD, chronic kidney disease, frameshift, genetic, urinary smear,
• MeSH
• Kidney Failure, Chronic epidemiology   genetics   pathology   MeSH
• Genes, Dominant * MeSH
• Adult MeSH
• Genetic Testing statistics & numerical data   MeSH
• Hepatocyte Nuclear Factor 1-beta genetics   MeSH
• Kidney Tubules pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-1 genetics   MeSH
• Mutation MeSH
• Prevalence MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Ireland epidemiology   MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-beta MeSH
• HNF1B protein, human MeSH Browser
• MUC1 protein, human MeSH Browser
• Mucin-1 MeSH
• UMOD protein, human MeSH Browser
• Uromodulin MeSH