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![Pedigree chart for subjects 29-1, 29-2, and 29-3. The identified heterozygous genetic variant COL4A3 p.Gly934Arg (G934R) was initially classified as a variant of unknown significance (VUS) (American College of Medical Genetics and Genomics [ACMG] criteria: PM1, PM2, PP3) but following segregation analysis was reclassified as likely pathogenic (ACMG: PM1, PM2, PP1, PP3). CKD chronic kidney disease, GFR glomerular filtration rate.](publication/339980828/figure/fig2/AS:870071949856768@1584452726052/Pedigree-chart-for-subjects-29-1-29-2-and-29-3-The-identified-heterozygous-genetic.png)
Pedigree chart for subjects 29-1, 29-2, and 29-3. The identified heterozygous genetic variant COL4A3 p.Gly934Arg (G934R) was initially classified as a variant of unknown significance (VUS) (American College of Medical Genetics and Genomics [ACMG] criteria: PM1, PM2, PP3) but following segregation analysis was reclassified as likely pathogenic (ACMG: PM1, PM2, PP1, PP3). CKD chronic kidney disease, GFR glomerular filtration rate.
Source publication
A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management.
Retrospective review of patients seen over a two-year period in the RGC.
One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known gen...
Context in source publication
Context 1
... additional studies including segregation analysis within an affected family can provide further evidence to support pathogenicity of the identified variant. We were able to demonstrate segregation of the identified variant in pedigree 19 and pedigree 29, which helped establish pathogenicity ( Figure 2). Sometimes, genetic variants that could explain the phenotype may be difficult to identify, as is the case with large gene segmental deletions or duplications that may not be detected with a standard bioinformatic pipeline. ...
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Background
Autosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exempt...
Citations
... DNA samples from these 70 SCD patients were processed by the University of Iowa Institute of Human Genetics for analysis by the 330-gene kidney panel, KidneySeq Version 5. 5 Pathogenic and moderate impact variants were identified using criteria developed by the American College of Medical Genetics and Genomics. 6,7 These genetic variants were further classified as involving glomerular, tubular, renin-angiotensin-aldosterone system (RAAS) or other functions based upon literature searches for the respective genes. The association between 0 and 2 versus 3 genetic variants involved in glomerular function with eGFR and urine ACR was performed by linear regression analysis adjusting for age, sex, hypertension and diabetes status using Systat 13 (Systat Software Corporation, Chicago, IL). ...
The pathophysiology and genetic risk for sickle cell disease (SCD)‐related chronic kidney disease (CKD) are not well understood. In 70 adults with SCD‐related CKD and without APOL1 inherited in a high‐risk pattern, 24 (34%) had pathogenic variants in candidate genes using KidneySeq™. A moderate impact INF2 variant was observed in 20 (29%) patients and those with 3 versus 0–2 pathogenic or moderate impact glomerular genetic variants had higher albuminuria and lower estimated glomerular filtration rate (adjusted p ≤ 0.015). Using a panel of preselected genes implicated in kidney health, we observed several variants in people with sickle cell nephropathy.
... Further underscoring the role of genetics, studies have demonstrated a surprisingly high prevalence of monogenic diseases even in patients with kidney disorders who do not have a known family history, as well as those presenting in adulthood, at ages across the lifespan [10,11]. This may be because affected family members remain unidentified owing to subtle expression or nonpenetrance of the disease, variable inheritance patterns, missing components of the family history, or de novo mutations [12,13]. In adult populations, family members may also not be as readily available for testing, limiting diagnostic capability despite a potential genetic factor [14]. ...
... In adult populations, family members may also not be as readily available for testing, limiting diagnostic capability despite a potential genetic factor [14]. Disorders of a monogenic etiology can also mimic phenotypes of acquired causes of renal pathology, leaving a genetic component overlooked [12]. ...
... For others, genetic testing can preclude the need for more invasive or expensive diagnostic approaches, such as kidney biopsy [24]. Additionally, more than 10% of adults newly diagnosed with ESKD have an unknown cause of their disease as earlier stages may be clinically silent and traditional diagnostics, including biopsy, may be contraindicated or no longer informative by the time these patients present [1,3,7,12,25]. Diagnostic genetic testing can also direct clinical management, guiding initiation of specific treatments or the avoidance of others, such as cases that allow forgoing ineffective long-term immunosuppression [19,26,27]. ...
The role of genetics in renal disorders is being increasingly recognized, prompting the need to describe and address barriers to meaningful implementation of genetic testing in clinical care.
The rapid expansion in accessibility and decreased cost of sequencing technologies has prompted increased identification of monogenic contributors to kidney disease and demonstration of the high yield of genetic testing in renal cohorts. Genetic testing in kidney disease and transplantation offers meaningful applications, including those relating to diagnosis, prognosis, management, and implications for family members and potential living donors. However, clinical implementation raises notable logistical, ethical, legal, and social considerations.
Chief among barriers and concerns are difficulties in variant interpretation, lack of adequate clinician training and genetic counseling availability, disparities in composition of reference databases, considerations in obtaining informed consent and returning genetic results, and concerns relating to privacy and legal protections. These considerations are not discrete and the complex issues among them overlap considerably, requiring multifaceted and adaptive interventions.
... In comparison, WES previously had diagnostic yields of 9.3%-60.0% in patients with CKD of unknown etiology or familial nephropathy, [5][6][7][8]22 [29][30][31][32] In one study, the overall diagnostic yield of WES in patients with cystic kidney disease was found to be 27%, with >90% of these patients having ADPKD due to variations in PKD1 and PKD2. 6 The present study did not include patients diagnosed with ADPKD by direct sequencing, and only 33% of patients with confirmed cystic disease/ciliopathy had ADPKD. ...
The genetic spectrum of genetic kidney diseases (GKD) and the application of genetic diagnoses to patient care were assessed by whole exome sequencing (WES) of the DNA of 172 pediatric or adult patients with various kidney diseases. WES diagnosed genetic diseases in 63 (36.6%) patients. The diagnostic yields in patients with glomerulopathy were 33.8% (25/74 pts) due to variants in 10 genes, 58.8% (20/34) in patients with tubulointerstitial disease due to variants in 18 genes, 33.3% (15/45) in patients with cystic disease/ciliopathy due to variants in 10 genes, 18.2% (2/11) in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) due to variants in two genes, and 12.5% (1/8) in patients with end stage kidney disease (ESKD). The diagnosis rate was high in patients aged <1–6 years (46–50.0%), and low in patients aged ≥40 years (9.1%). Renal phenotype was reclassified in 10 (15.9%) of 63 patients and clinical management altered in 10 (15.9%) of 63 patients after genetic diagnosis. In conclusion, these findings demonstrated the diagnostic utility of WES and its effective clinical application in patients, with various kinds of kidney diseases, across the different age groups.
... As an answer to the constantly increasing demand of genetic testing in patients with CKD, organizations and healthcare systems have been trying to set up service delivery models for the optimization of genomic strategies into routine practice (55). Although providing significantly different results, these preliminary experiences agree upon the clinical utility of genetic testing in patients with kidney diseases and CKD (49,50,(56)(57)(58)(59)(60). An economic evaluation showed that early ES is effective in diagnosing monogenic kidney disease and leads to substantial cost savings in children with glomerular disorders (49,61). ...
Chronic kidney disease (CKD) is a major healthcare issue worldwide. However, the prevalence of pediatric CKD has never been systematically assessed and consistent information is lacking in this population. The current definition of CKD is based on glomerular filtration rate (GFR) and the extent of albuminuria. Given the physiological age-related modification of GFR in the first years of life, the definition of CKD is challenging per se in the pediatric population, resulting in high risk of underdiagnosis in this population, treatment delays and untailored clinical management. The advent and spreading of massive-parallel sequencing technology has prompted a profound revision of the epidemiology and on the causes of CKD in children, supporting the hypothesis that CKD is much more frequent than currently reported in children and adolescents. This acquired knowledge will eventually converge in the identification of the molecular pathways and cellular response to damage, with new specific therapeutic targets to control disease progression and clinical features of children with CKD. In this review, we will focus on recent innovations in the field of pediatric CKD and in particular those where advances in knowledge have become available in the last years, to the aim of providing a new perspective on CKD in children and adolescents.
... Inclusion of CGCs, partnerships with clinicians and genomic experts outside of nephrology to provide support in the light of a diagnosis along with education of patients and families about the significance of the genetic test and its outcomes helped improve diagnostic rates and elevate patient care and disease management. [62][63][64][65][66] The comparative increase in insufficient or contradictory evidence has limited the efficacy of genomic diagnostics in a clinical context. 28 This has been either due to lack of relevance in diagnostic accuracy or due to misclassification of variants when associating rare variants (stemming from small sample sizes). ...
This year marks the 61st anniversary of the International Society of Nephrology, which signaled nephrology's emergence as a modern medical discipline1. In this article, we briefly trace the course of nephrology's history to show a clear arc in its evolution - of increasing resolution in nephrological data - an arc that is converging with computational capabilities to enable precision nephrology. In general, precision medicine refers to tailoring treatment to the individual characteristics of patients2. For an operational definition, this tailoring takes the form of an optimization, in which treatments are selected to maximize a patient's expected health with respect to all available data. Because modern health data is large and high resolution, this optimization process requires computational intervention, and it must be tuned to the contours of specific medical disciplines. An advantage of this operational definition for precision medicine is that it allows us to better understand what precision medicine means in the context of a specific medical discipline. The goal of this article is to demonstrate how to instantiate this definition of precision medicine for the field of nephrology. In brief, the goal of precision nephrology becomes answering two related questions: (1) How do we optimize kidney health with respect to all available data? and (2) How do we optimize general health with respect to kidney data?
... The progressive decline in sequencing costs led this technology to subsequently spread also in clinical settings to unravel the etiology of kidney phenotypes, although consensus criteria on which patients should undergo WES have not been reached yet. [10][11][12][13][14][15][16][17][18] Studies on the utility of WES in patients with kidney diseases mostly relate to highly selected cohorts of patients (e.g., steroid-resistant nephrotic syndrome, distal renal tubular acidosis) in single-center or registry-based approaches. Selection criteria were usually stringent and phenotype-centered. ...
... Setting up service delivery models that empower timely and cost-efficient access to genetic testing and counseling is important but challenging. Several studies described such service delivery models in clinics for genetic kidney diseases, [10][11][12]15 reporting diagnostic yields of 10%-40% and benefits at the single-patient level, but low cost-effectiveness. 10,29 In this study, we report on a workflow that led to a diagnostic rate as high as 67.0% in patients of all ages affected by different types of kidney diseases and was ultimately cost-saving. ...
... First, our study population is restricted geographically (89% of patients were Europeans, mostly coming from Italy), although comparable with those reported in previous studies. 10,[12][13][14][15] Second, we could not perform either cost-effectiveness analysis or cost-utility analysis modeling quality-adjusted life-years that are used in economic settings as an outcome measure of health benefits. 58 Consequently, future studies are needed to address these issues. ...
Background:
Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice.
Methods:
Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion.
Results:
We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%.
Conclusions:
A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.
... 14,15 There is an increasing demand for renal genetics clinics, and relatively long-term studies in Australia, England, and Ireland have demonstrated multidisciplinary renal genetics clinics improve the patient diagnosis and management outcomes, [16][17][18] but only a few medical centers have this service available in the United States. 12,19,20 Further, genetic testing is often performed in a research setting. 21 Data from real-world daily practice of renal genetics clinics is limited. ...
... 21 Data from real-world daily practice of renal genetics clinics is limited. 12,19 The renal genetics clinic of the Cleveland Clinic was initiated in December 2018, and is led by a physician with dual roles as nephrologist and medical geneticist, which is uncommon. All patients undergo a thorough evaluation from nephrology and genetics, with testing performed in Clinical Laboratory Improvement Amendments-certified labs. ...
... The variable presentations of patients in the renal genetics clinic represent all aspects of clinical nephrology. Compared to other renal genetics clinics 16,19,26 where cystic kidney disease was cited as the most common clinical presentation, the large number of referrals for glomerular disease in our patient population reflects the diagnostic complexity in an academic referral center providing comprehensive specialty care comprised of subspecialized nephrology clinics, virtual pathology consultations, kidney transplants, and an infusion center. The increasing pursuit of a genetic diagnosis in glomerular diseases also underscores its clinical relevance in preventing invasive kidney biopsies, avoiding deleterious effects of ineffective long-term immunosuppression, and evaluating risks for related living donors. ...
Rationale & Objective
There has been an increasing demand for the expertise provided by a Renal Genetics Clinic. Such programs are limited in the US and typically operate in a genomics research setting. Here we report a three year, real world, single center renal genetics clinic experience.
Study Design
Retrospective cohort.
Setting & Participants
Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed.
Analytical Approach
Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs.
Results
309 new patients referred from 15 specialties were evaluated including 118 males and 191 females aged 35.1±20.3 years old. Glomerular diseases are the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 patients (94.5%) including chromosomal microarray (8.9%), single gene tests (19.5%), multi-gene panels (77.3%), and exome sequencing (17.5%). 80.5% patients received insurance coverage for genetic testing. Forty-five percent (115/256) patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) negative results. Forty-three distinct monogenic disorders were diagnosed. Family history of kidney disease is present in 52.8% patients and associated with positive genetic findings (odds ratio 2.28 (1.40-3.74)). Sixty-nine percent of patients with positive results received a new diagnosis and or a change in the diagnosis. Among these, 39.7% (31 out of 78) patients received a significant change in disease management.
Limitations
Retrospective and single center study.
Conclusions
The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multi-gene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.
... As we prepare to mainstream genomic testing into nephrology practice, there is paucity of data that evaluate the barriers to genomic implementation within nephrology [12]. Previous work in other specialty areas has explored barriers; however, few have used theory informed methods and focus, instead, on clinical knowledge and education [12,14,15]. Within nephrology, previous research assessed nephrologists' attitudes and practices, as well as perceived barriers and interventions to the uptake of genomic medicine through a mixed methods electronic survey [16]. ...
Background: (1) Background: Genomic testing is increasingly utilized as a clinical tool; however, its integration into nephrology remains limited. The purpose of this study was to identify barriers and prioritize interventions for the widespread implementation of genomics in nephrology. (2) Methods: Qualitative, semi-structured interviews were conducted with 25 Australian adult nephrologists to determine their perspectives on interventions and models of care to support implementation of genomics in nephrology. Interviews were guided by a validated theoretical framework for the implementation of genomic medicine—the Consolidated Framework of Implementation Research (CFIR). (3) Results: Nephrologists were from 18 hospitals, with 7 having a dedicated multidisciplinary kidney genetics service. Most practiced in the public healthcare system (n = 24), a large number were early-career (n = 13), and few had genomics experience (n = 4). The top three preferred interventions were increased funding, access to genomics champions, and education and training. Where interventions to barriers were not reported, we used the CFIR/Expert Recommendations for Implementing Change matching tool to generate theory-informed approaches. The preferred model of service delivery was a multidisciplinary kidney genetics clinic. (4) Conclusions: This study identified surmountable barriers and practical interventions for the implementation of genomics in nephrology, with multidisciplinary kidney genetics clinics identified as the preferred model of care. The integration of genomics education into nephrology training, secure funding for testing, and counselling along with the identification of genomics champions should be pursued by health services more broadly.
... However, with the value of genetic testing evident, health care system implementation is trying to parallel clinical enthusiasm. Indeed, in the last few years, there has been a bloom in service delivery models for optimizing genomic investigations in patients with kidney diseases, commonly referred to as "renal genetic clinics" (RGCs, Table 1) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Usually designed as multidisciplinary groups, RCGs aim at integrating different expertise in answering the complex question: is there a genetic cause behind this clinical picture? ...
... Consequently, in RGCs there is close collaboration between nephrologists and geneticists to address this point and different examinations are used (Table 1). Although singlegene and target-gene panel sequencing are commonly used (5,(7)(8)(9)(10)(11)(12)15,17), WES (comprising WES-based panels, clinical WES, and full WES) is progressively replacing phenotypecentered approaches (6,10), especially for oligogenic IKD. The progressive decline in costs would probably empower WES as a first-line genetic approach, increasing the need to adopt strategies to deal with unexpected findings and variants of unknown clinical significance. ...
... Disease reclassification occurs at a frequency of 13%-39% in the studies reporting the experience of RGCs so far, and is in line with previous reports on the use of genetic testing in different populations for research purposes (16). Disease reclassification and identification of phenocopies have important implications for clinical management, including prognosis prediction and tailoring therapies (5)(6)(7)(8)(11)(12)(13). Joining different expertise in multidisciplinary boards is adopted to address these issues and to identify results worthy to be reported to patients and families through post-testing counseling. ...
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... The use of genomic sequencing in routine clinical care allows for vastly improved diagnostic yields for genetic kidney disease [1,2]. The yield is in the order of 30-60% combining adult and paediatric contexts [1][2][3]. Genomic sequencing technology benefits patients in a clinical diagnostic context through accurate clinical diagnosis, informing management, and familial implications [1,2]. In one Australian study, 39% of kidney disease patients had a change in their clinical diagnosis, with 56% having a change to their clinical management, such as: 13% avoiding the need for diagnostic renal biopsy, 44% changing surveillance, and 20% changing the treatment plan. ...
Background: The choices of participants in nephrology research genomics studies about receiving additional findings (AFs) are unclear as are participant factors that might influence those choices. Methods: Participant choices and factors potentially impacting decisions about AFs were examined in an Australian study applying research genomic testing following uninformative diagnostic genetic testing for suspected monogenic kidney disease. Results: 93% of participants (195/210) chose to receive potential AFs. There were no statistically significant differences between those consenting to receive AFs or not in terms of gender (p = 0.97), median age (p = 0.56), being personally affected by the inherited kidney disease of interest (p = 0.38), or by the inheritance pattern (p = 0.12–0.19). Participants were more likely to choose not to receive AFs if the family proband presented in adulthood (p = 0.01), if there was family history of another genetic disorder (p = 0.01), and where the consent process was undertaken by an adult nephrologist (p = 0.01). Conclusion: The majority of participants in this nephrology research genomics study chose to receive potential AFs. Younger age of the family proband, family history of an alternate genetic disorder, and consenting by some multidisciplinary team members might impact upon participant choices.
