Genetic Testing in Nephrology: Show Your Pedigree!

The Experience of Renal Genetic Clinics in the Real World

Genomic medicine has been revolutionizing our approach to health problems and disease pathophysiology. Increasing evidence suggests that inherited kidney disorders (IKD) represent a leading cause of CKD and kidney failure, either in children or adults (1).

Given the extremely high complexity of kidney architecture, the genetics of kidney diseases are heterogeneous, and the number of genes responsible for IKD constantly rising (2). The spread of second- and third-generation sequencing (e.g., massive-parallel sequencing, MPS) technologies from research laboratories to diagnostic facilities is pushing genetics and genomics outside the domain of geneticists and basic science researchers toward clinical departments (3,4). MPS approaches (e.g., targeted gene panel whole-exome sequencing, WES; whole-genome sequencing, WGS) do not strictly require the precise genetic diagnosis to be formulated on the basis of the clinical phenotype, which can be not infrequently misleading, because they cover larger parts of DNA (5). Moreover, the constant decrease in costs and turnaround times related to sequencing is an additional benefit that makes genetic testing suitable for daily clinical practice. As a result, clinicians are asked to become increasingly familiar with ordering genetic testing and translating results to patient care (e.g., tailoring treatments and clinical investigations, assessing kidney donor eligibility, providing family counseling, etc.), potentially reducing the clinical uncertainty of CKD diagnosis (1,3,6). Consequently, the number of patients who should be considered for genetic testing is rapidly requiring health care systems to address the increased need for personalized medicine. Accessibility to genetic testing, ordering the appropriate variant prioritization, interpretation of results, integration into the clinical decision-making process, and cost concerns can potentially limit the widespread use of genomic medicine in routine practice (3,4). 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) (5–15). 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? In other words, RGCs represent the attempt to solve the “five Ws” (whom, what, where, when, why) question to gather information about the potential genetic cause of kidney diseases, with important implications for clinical management and prognosis.

Table 1.

Summary of the results of studies reporting the experience of renal genetic clinics

Ref	Patients (n)	Reason for Referral	Diagnostic Yield (%)	Genetic Examination	Data Interpretation	FamilialPatients (%)	Population	Diagnosis Reclassification (%)	Clinical Utility (%)
Elhassan et al., 2021 (7)	677	-CKD and family history -Extrarenal features or uCKD	51	WGS, WES, gene panel	Nephrologist, clinical geneticist, bioinformatic	74	Adult	13	47
Jayasinghe et al., 2021 (6)	204	-Family history -Early onset -Extrarenal manifestations	39	WES, CMA	Laboratory scientist, clinical geneticist, nephrologist	50	Adult (60%), children (40%)	39	59
Thomas et al., 2020 (8)	65	—	40	Gene panel	Adult and pediatric nephrologist, genetic counselors	—	Adult, children	—	6
Tanudisastro et al., 2021 (9)	552	—	35	Gene panel, WES-based panel	Nephrologists, clinical geneticists, laboratory scientist	2	Adult (49%), children (51%)	—	—
Pode-Shakked et al., 2022 (10)	74	-uCKD -Transplant counseling -Genetic counseling after positive findings	57	Sanger, gene panel, CMA, WES	Adult and pediatric nephrologists, clinical geneticists, genetic counselors, bioinformatics scientists	—	Adult, children	—	—
Lundquist et al., 2022 (11)	19	—	47	Gene panel, WES-based panel	Nephrologist, genetic counselor	—	Adult	—	16
Bogyo et al., 2022 (12)	279	-Clarify a clinical diagnosis -Clarification of biopsy finding -Transplant counseling -Cascade family genetic testing	27	Single variant and single gene sequencing, gene panel, CMA, WES	Nephrologists, geneticists, genetic counselors, genetics researchers	25	Adult	—	16
Amlie-Wolf et al., 2021 (13)	86	—	33	—	Nephrologist, genetic counselor	17	Adult	—	31
Mallett et al., 2016 (14)	83	—	39	—	Geneticist, nephrologist, genetic counselor	7	Adult, children	25	—
Alkanderi et al., 2017 (15)	62	-Suspected familial hematuria -Suspected cystic disease	42	Single gene sequencing, gene panel	Clinical geneticist, adult and pediatric nephrologist	—	Adult (38%), children (62%)	—	—
Pinto E Vairo et al., 2021 (17)	163	—	31	Targeted panels, single-gene sequencing, WES-based panel	Nephrologists, geneticists, pathologists, translational omics scientists	—	Adult (77%), children (23%)	25	100

uCKD, CKD of unknown etiology; WES, whole exome sequencing; WGS, whole genome sequencing; CMA, chromosomal microarray.

Whom to Test?

Patient selection and referral to the RGCs is emerging as critical for ensuring the optimization of service delivery models for the genetic diagnosis of IKD. Targeting the right population to screen actually has a profound effect on the diagnostic yields, which range from 27% to 57% in the studies published so far (Table 1). This is becoming particularly relevant because clinician awareness about IKD is spreading, and genetic testing is increasingly considered a tool in the diagnostic trajectory of patients with kidney diseases. Nephrologists, geneticists, and genetic counselors are in charge of patient selection, pretest counseling, and offering genetic testing, according to local policies and laws. Early onset of the clinical phenotype, familial history of kidney diseases, and extrarenal involvement usually flank more disease-specific clinical criteria (e.g., resistance to steroids in patients with nephrotic syndrome, polycystic kidney disease, etc.) to prioritize access to genetic testing (1,3,4). CKD of unknown origin, which is reported to account for 10%–40% of patients with CKD in the adult population, represents an additional indication of genetic testing in many studies (16). Of note, genetic testing is often ordered in patients with an unspecified clinical suspicion of IKD (i.e., “referral to RGC,” see Table 1) and clinicians’ expertise and sensitivity represents the guiding criterion. Therefore, robust, widely applicable, prespecified clinical criteria are still a matter of debate, potentially preventing nonexpert clinicians from appropriately referring patients for genetic screening; very recently, general indications to suspect genetic disease have been suggested (Figure 1) (1,3,4).

Figure 1.

Renal genetic clinic typical workup.

What Test Should be Used?

The advent of the genomic era fostered an impressive improvement in the knowledge of the molecular basis of kidney diseases, that can be caused by single nucleotide variants, genomic imbalances (copy number variations, or other rearrangements), and, more rarely, from chromosomal abnormalities (2). As a result, choosing the right type of genetic testing to ascertain a genetic diagnosis of IKD is as pivotal as it is delicate, with relevant effect on the diagnostic rate. Although geneticists are familiar with the need of tailoring genetic investigations to the clinical questions, nephrologists usually are not. Consequently, in RGCs there is close collaboration between nephrologists and geneticists to address this point and different examinations are used (Table 1). Although single-gene and target-gene panel sequencing are commonly used (5,7–12,15,17), WES (comprising WES-based panels, clinical WES, and full WES) is progressively replacing phenotype-centered 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. More detailed indications on which test should be used according to clinical suspicion have been suggested (3). Of note, nontargeted testing for copy number variations are seldom reported in RGCs, probably leading to an underestimation of the diagnostic rate. Due to a high economic burden and technical issues, only a few studies used WGS. In the future, WGS will serve as an additional tool to explore uncovered genomic regions and to increase the performance of genetic investigations.

Where to Perform Genetic Testing?

Providing patients and families with a conclusive genetic diagnosis is less achievable through sequencing alone. MPS markedly increases the risk of unexpected findings, requiring appropriate strategies to deal with the clinical relevance of the results of sequencing. Deep phenotyping, variant segregation within the family, and database interrogation are usually put in place for variant interpretation and pathogenicity scoring. In selected patients, functional testing (e.g., expression studies) and in vivo and in vitro disease modeling can be considered for reaching a conclusive diagnosis, according to the availability of research infrastructures and funding. These additional analyses can allow variant prioritization, obtaining a conclusive genetic diagnosis and revising the clinical analysis (5–7,14). 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 (5–8,11–13). 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. The composition of multidisciplinary boards can be quite variable (Table 1). The availability of all of the expertise required, the need of continuous technological implementation, and professional training imposes to design tertiary centers that can afford and sustain the work of multidisciplinary groups in RGCs. Although various companies offer on-demand genetic testing for many IKD, the incorporation of the results into the appropriate clinical context is indisputably relevant.

When to Test?

IKD are a leading cause of CKD in children. However, increasing evidence suggests they can be diagnosed across all age groups, pointing toward the opportunity to downgrade age as critical for genetic diagnosis (1). Many studies reporting on RGC models included adult patients in the study population (5–9,14,15,17), and a few even excluded children (11–13). Interestingly, the diagnostic rate did not significantly differ in the two populations, supporting the need to consider genetic testing independently from the age at onset of kidney disease, whenever IKD are suspected on the basis of the clinical picture. This observation strengthens the appropriateness of establishing service delivery models that empower required expertise, technologies, and tools, irrespective of the assignment to a pediatric or adult health care provider.

Reimbursement policies, funding programs, and health care system organizations can influence the access to genetic testing and its timing. Although insurance companies are increasingly aware of the value of genetic testing in the suspicion of IKD, coverage still represents an issue limiting genetic diagnosis. This is particularly relevant for, but not limited to, full private or insurance-based health care systems. Clinicians must inform patients about the “nontraditional utility” of genetic testing, including psychosocial, ethical, and legal effects (18). Indeed, a positive genetic test can have implications on the subsequent perception of quality of life and change the conditions of accessibility to insurance. For children, in particular, the timing is still a matter of debate for those diseases where effective treatments are not available, or when preventive actions cannot be initiated before adulthood (3,19). In contrast, presymptomatic testing may provide suggestions and reproductive options to prevent passing the disease to new generations (e.g., prenatal diagnosis or preimplantation genetic testing) (1). In this view, genetic counseling is pivotal to support patients and families in the decision-making process.

Why to Test?

A conclusive genetic diagnosis has the potential to refine clinical trajectories by ending the “diagnostic odyssey,” promoting awareness of therapeutic choices, and establishing the appropriate work-up, thus offering a host of benefits to patients and families. The clinical utility of genetic testing has been claimed from all of the studies reporting experience of RGCs in clinical settings (Table 1).

A further step in integrating RGCs into daily clinical practice is represented by assessing cost effectiveness. Policymakers and health care providers prioritize resource allocation, balancing the benefits of disease diagnosis with the economic efforts to be sustained. The substantial reduction in costs of MPS is paralleled by a burdensome increase in time and economic expenses for large dataset management and variant interpretation, thus questioning affordability. Longitudinal studies of large cohorts of individuals with genetically confirmed IKD are required to conclusively assess the effect of translating genetic findings into improved patient care, the effect of health care systems, and outcomes.

In conclusion, first experiences of RGCs strongly support the benefits of integrated service-delivery models that can balance economic and organizational needs with clinical utility. Ordering genetic testing, genetic data interpretation, results reporting, and counseling is burdensome, claiming for the optimization of resources, defining key performance indicators of the activity, and providing continuous evidence of clinical utility of genetic results in real-world nephrology settings.

Disclosures

All authors have nothing to disclose.

Funding

None.

Author Contributions

F. Becherucci and L. Cirillo conceptualized the study; F. Becherucci and L. Cirillo were responsible for the methodology; F. Becherucci provided supervision; L. Cirillo was responsible for the visualization; L. Cirillo wrote the original draft; F. Becherucci reviewed and edited the manuscript.