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Introduction: Genomic medicine holds transformative potential for personalized nephrology care; however, its clinical integration poses challenges. Automated clinical decision support (CDS) systems in the electronic health record (EHR) offer a promising solution but have shown limited impact. This study aims to glean practical insights into nephrologists' challenges using genomic resources, informing precision nephrology decision support tools. Methods: We conducted an anonymous electronic survey among US nephrologists from January 19, 2021 to May 19, 2021, guided by the Consolidated Framework for Implementation Research. It assessed practice characteristics, genomic resource utilization, attitudes, perceived knowledge, self-efficacy, and factors influencing genetic testing decisions. Survey links were primarily shared with National Kidney Foundation members. Results: We analyzed 319 surveys, with most respondents specializing in adult nephrology. Although respondents generally acknowledged the clinical use of genomic resources, varying levels of perceived knowledge and self-efficacy were evident regarding precision nephrology workflows. Barriers to genetic testing included cost/insurance coverage and limited genomics experience. Conclusion: The study illuminates specific hurdles nephrologists face using genomic resources. The findings are a valuable contribution to genomic implementation research, highlighting the significance of developing tailored interventions to support clinicians in using genomic resources effectively. These findings can guide the future development of CDS systems in the EHR. Addressing unmet informational and workflow support needs can enhance the integration of genomics into clinical practice, advancing personalized nephrology care and improving kidney disease outcomes. Further research should focus on interventions promoting seamless precision nephrology care integration.
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About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.
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Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides "regional AF" (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as "rAF-hi" indels. Notably, a high percentage of rare indels were "rAF-hi", with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels' parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.
Subject(s)
Gene Frequency , INDEL Mutation , Humans , AlgorithmsABSTRACT
Cardiovascular disease, infection, malignancy, and thromboembolism are major causes of morbidity and mortality in kidney transplant recipients (KTR). Prospectively identifying monogenic conditions associated with post-transplant complications may enable personalized management. Therefore, we developed a transplant morbidity panel (355 genes) associated with major post-transplant complications including cardiometabolic disorders, immunodeficiency, malignancy, and thrombophilia. This gene panel was then evaluated using exome sequencing data from 1590 KTR. Additionally, genes associated with monogenic kidney and genitourinary disorders along with American College of Medical Genetics (ACMG) secondary findings v3.2 were annotated. Altogether, diagnostic variants in 37 genes associated with Mendelian kidney and genitourinary disorders were detected in 9.9% (158/1590) of KTR; 25.9% (41/158) had not been clinically diagnosed. Moreover, the transplant morbidity gene panel detected diagnostic variants for 56 monogenic disorders in 9.1% KTRs (144/1590). Cardiovascular disease, malignancy, immunodeficiency, and thrombophilia variants were detected in 5.1% (81), 2.1% (34), 1.8% (29) and 0.2% (3) among 1590 KTRs, respectively. Concordant phenotypes were present in half of these cases. Reviewing implications for transplant care, these genetic findings would have allowed physicians to set specific risk factor targets in 6.3% (9/144), arrange intensive surveillance in 97.2% (140/144), utilize preventive measures in 13.2% (19/144), guide disease-specific therapy in 63.9% (92/144), initiate specialty referral in 90.3% (130/144) and alter immunosuppression in 56.9% (82/144). Thus, beyond diagnostic testing for kidney disorders, sequence annotation identified monogenic disorders associated with common post-transplant complications in 9.1% of KTR, with important clinical implications. Incorporating genetic diagnostics for transplant morbidities would enable personalized management in pre- and post-transplant care.
Subject(s)
Exome Sequencing , Genetic Testing , Kidney Transplantation , Humans , Kidney Transplantation/adverse effects , Genetic Testing/methods , Female , Male , Adult , Middle Aged , Postoperative Complications/genetics , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Transplant Recipients/statistics & numerical data , Aged , Genetic Predisposition to DiseaseABSTRACT
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-ß functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
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AIDS-Associated Nephropathy , Glomerulosclerosis, Focal Segmental , Renal Insufficiency , Telomerase , Adult , Humans , Mice , Animals , Glomerulosclerosis, Focal Segmental/pathology , Telomerase/therapeutic use , AIDS-Associated Nephropathy/pathology , Proteinuria , Renal Insufficiency/complications , Disease Models, AnimalABSTRACT
African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry.
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Graft Rejection , Graft Survival , Kidney Transplantation , Self Report , Humans , Male , Female , Middle Aged , Graft Rejection/genetics , Graft Rejection/etiology , Graft Survival/genetics , Risk Factors , Adult , Prognosis , Follow-Up Studies , Urban Population , Black or African American/genetics , Kidney Failure, Chronic/surgery , Kidney Failure, Chronic/genetics , Transplant Recipients , Ethnicity/genetics , Neighborhood Characteristics , Glomerular Filtration Rate , Kidney Function Tests , Cohort StudiesABSTRACT
OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.
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Heart Defects, Congenital , Kidney Diseases , Urogenital Abnormalities , Female , Humans , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/genetics , Kidney/abnormalities , Kidney Diseases/congenital , Neoplasm Proteins/genetics , Urogenital Abnormalities/geneticsABSTRACT
Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10-4 for dominant disorders and MAF ≤ 10-3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06-8.18, p value = 4.5e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.
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Kidney Diseases , Liver Diseases , Humans , Exome Sequencing , Gene Frequency , Phenotype , Liver Diseases/diagnosis , Liver Diseases/geneticsABSTRACT
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Subject(s)
Polycystic Kidney, Autosomal Dominant , Renal Insufficiency, Chronic , Humans , Penetrance , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/complications , Multifactorial Inheritance/genetics , Risk FactorsABSTRACT
SIGNIFICANCE STATEMENT: Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management. BACKGROUND: Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated. METHODS: Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113 ) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed. RESULTS: Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18-96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients. CONCLUSIONS: Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05846113 .
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Renal Insufficiency, Chronic , Humans , Adult , Adolescent , Young Adult , Middle Aged , Aged , Aged, 80 and over , Prospective Studies , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/therapy , Genetic TestingABSTRACT
PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. RESULTS: Results demonstrate â¼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to â¼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.
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Epilepsy , Urinary Tract , Urogenital Abnormalities , Animals , Mice , Humans , Penetrance , Mice, Inbred C3H , Mice, Inbred C57BL , Urogenital Abnormalities/genetics , Kidney/abnormalities , Risk Factors , Epilepsy/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/geneticsABSTRACT
Introduction: The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods: We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results: We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion: Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.
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Background: Chronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors. Methods: Using the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in the PKD1 or PKD2 genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants in COL4A3, COL4A4, or COL4A5 genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry. Results: As expected, the carriers of known pathogenic and rare predicted loss-of-function variants in PKD1 or PKD2 had a high risk of CKD (ORmeta=17.1, 95% CI: 11.1-26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (ORmeta=2.28 per SD, 95%CI: 1.55-3.37, P=2.6E-05) and non-carriers (ORmeta=1.72 per SD, 95% CI=1.69-1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (ORmeta=1.78, 95% CI=1.22-2.58, P=2.38E-03) and non-carriers (ORmeta=1.70, 95%CI: 1.68-1.73 P
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Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
Subject(s)
Genome-Wide Association Study , Nephrotic Syndrome , Humans , Child , Nephrotic Syndrome/genetics , Genetic Predisposition to Disease , Haplotypes , Risk Factors , Polymorphism, Single NucleotideABSTRACT
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder causing symptoms of urinary frequency, urgency, and bladder discomfort or pain. Although this condition affects a large population, little is known about its etiology. Genetic analyses of whole exome sequencing are performed on 109 individuals with IC/BPS. One family has a previously reported SIX5 variant (ENST00000317578.6:c.472G>A, p.Ala158Thr), consistent with Branchiootorenal syndrome 2 (BOR2). A likely pathogenic heterozygous variant in ATP2A2 (ENST00000539276.2:c.235G>A, p.Glu79Lys) is identified in two unrelated probands, indicating possible Darier-White disease. Two private heterozygous variants are identified in ATP2C1 (ENST00000393221.4:c.2358A>T, p.Glu786Asp (VUS/Likely Pathogenic) and ENST00000393221.4:c.989C>G, p.Thr330Ser (likely pathogenic)), indicative of Hailey-Hailey Disease. Sequence kernel association test analysis finds an increased burden of rare ATP2C1 variants in the IC/BPS cases versus a control cohort (p = 0.03, OR = 6.76), though does not survive Bonferroni correction. The data suggest that some individuals with IC/BPS may have unrecognized Mendelian syndromes. Comprehensive phenotyping and genotyping aid in understanding the range of diagnoses in the population-based IC/BPS cohort. Conversely, ATP2C1, ATP2A2, and SIX5 may be candidate genes for IC/BPS. Further evaluation with larger numbers is needed. Genetically screening individuals with IC/BPS may help diagnose and treat this painful disorder due to its heterogeneous nature.
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BACKGROUND: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors. METHODS: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation. RESULTS: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups. CONCLUSIONS: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function.
Subject(s)
Glomerulosclerosis, Focal Segmental , Humans , Glomerulosclerosis, Focal Segmental/genetics , Glomerulosclerosis, Focal Segmental/diagnosis , Apolipoprotein L1/genetics , Cohort Studies , Risk Factors , Genotype , Apolipoproteins/geneticsABSTRACT
PURPOSE: The success of genomic medicine hinges on the implementation of genetic knowledge in clinical settings. In novel subspecialties, it requires that clinicians refer patients to genetic evaluation or testing, however referral is likely to be affected by genetic knowledge. METHODS: An online survey was administered to self-identified nephrologists working in the United States. Nephrologists' demographic characteristics, genetic education, confidence in clinical genetics, genetic knowledge, and referral rates of patients to genetic evaluation were collected. RESULTS: In total, 201 nephrologists completed the survey. All reported treating patients with genetic forms of kidney disease, and 37% had referred <5 patients to genetic evaluation. A third had limited basic genetic knowledge. Most nephrologists (85%) reported concerns regarding future health insurance eligibility as a barrier to referral to genetic testing. Most adult nephrologists reported insufficient genetic education during residency (65%) and fellowship training (52%). Lower rating of genetic education and lower knowledge in recognizing signs of genetic kidney diseases were significantly associated with lower number of patients referred to the genetic evaluation (P < .001). Most nephrologists reported that improving their genetic knowledge is important for them (>55%). CONCLUSIONS: There is a need to enhance nephrologists' genetic education to increase genetic testing use in nephrology.
Subject(s)
Kidney Diseases , Nephrology , Adult , Humans , United States , Nephrologists , Nephrology/education , Surveys and Questionnaires , Referral and Consultation , Attitude of Health PersonnelABSTRACT
SIGNIFICANCE STATEMENT: APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity. BACKGROUND: APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers. METHODS: We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set-based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD. RESULTS: Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90). CONCLUSIONS: In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.
Subject(s)
Apolipoprotein L1 , Renal Insufficiency, Chronic , Humans , Apolipoprotein L1/genetics , Inflammasomes , Renal Insufficiency, Chronic/genetics , Genotype , Risk , Genetic Predisposition to Disease , Risk FactorsABSTRACT
SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk. CONCLUSION: Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.