Kidney Genetics: Continuing Discoveries and a Roadmap to the Clinic

Podcast

This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_03_JASN2022060725.mp3

The genetic architecture associated with monogenic (Mendelian) and CKD continues to be characterized in increasing granularity with the widespread use of massively parallel sequencing methodologies. As these discoveries mount, the demand for translation of CKD genomic diagnostics into the clinic has grown. In this issue of the Journal of the American Society of Nephrology, new work rigorously shows genetic variants known as copy number variants (CNVs) associate across the lifespan with monogenic CKD.¹ A second study provides a compelling implementation roadmap for incorporation of monogenic CKD genomic diagnostics into the clinic.²

At least 625 genes are known to cause monogenic kidney diseases.³ The estimated prevalence of monogenic kidney diseases is 70%, and 10%–15% in pediatric and adult populations, respectively.⁴ However, a significant proportion of the genetic risk for CKD remains unexplained. Genetic traits include loss (deletions) or gain (duplication or higher) of genomic DNA, which are collectively described as CNV. These CNVs cause clinical genomic disorders. Verbitsky et al.¹ analyzed the association of CNV in a pediatric CKD cohort with 661 cases and in three adult cohorts with 6927 subjects with CKD in aggregate. As already known, genomic disorders were enriched in children with CKD, with a prevalence of 4% compared with <1% in a control group. More unexpectedly, genomic disorders were statistically enriched in adults with CKD with a prevalence of 1%.

Genomic disorders are frequently syndromic and can involve more than one organ system. Phenotypic association analyses in two independent cohorts confirmed the association of genomic disorders with CKD, impaired neurocognition and other comorbidities, suggesting that symptoms attributed to CKD in some individuals may be caused by an underlying genetic disorder rather than diminished kidney function. Finally, CNV carriers had increased risk of mortality compared with noncarriers. An analysis of UK Biobank adult participants has also shown that kidney failure and increased mortality were associated with CNV carrier state.⁵ Therefore, detection of genomic disorders associated with CKD provides a molecular diagnosis, may inform prognosis, and can affect the management of associated neuropsychiatric disease and other comorbidities. This study also demonstrates the value of exome sequencing, as opposed to genotyping or targeted gene or gene-set sequencing, in facilitating discovery of genetic trait associations by permitting iterative analyses of DNA sequences from a CKD cohort when new data emerge.

As the genetic architecture underlying CKD has become more clearly defined, CKD genomic diagnostics have also become commercially available. Yet, data supporting best practices for use of these tests in the care of people with kidney diseases are limited, with enthusiasm for genetic testing exceeding the evidence for optimal implementation. Both the Kidney Disease Improving Global Outcomes⁶ and the National Kidney Foundation have gathered experts to develop principles for and identify knowledge gaps in the implementation of genetic testing. Workflows, solve rates (which range from 10% to 70%), and clinical utility of genetic diagnosis have been reported for several kidney genetic clinics in large academic centers,^7,8 but these reports do not systematically address the approaches and challenges of genetic testing in a nephrology practice.

A second study in this issue describes a clinical workflow for diagnosis of monogenic kidney diseases, tests its performance, and assesses its cost-effectiveness.² Becherucci and her coworkers first analyzed a historical cohort of 392 patients with CKD who had exome sequencing and identified seven clinical criteria that predicted a genetic diagnosis. They then established a regional network in Italy that prospectively referred patients with suspected genetic diseases and at least one selection criterion to a central center to establish a genetic diagnosis. Exome sequencing, reverse phenotyping, and multidisciplinary board discussion were key components of the diagnostic pipeline.

A genetic diagnosis was made in 37% of the retrospective cohort, which increased to 67% of cases in the prospective cohort. The clinical diagnosis was confirmed in 48% of the prospectively studied patients, and the remaining 19% were reclassified to a new diagnosis. The diagnostic success rate was nearly equivalent in adult and pediatric cases. Similar to earlier reports, establishing a genetic diagnosis had beneficial impact on clinical management, including establishing a prognosis, identifying and monitoring family members at risk for CKD, referring probands to clinical trials, informing kidney donor selection, and providing counseling for family planning. Critically, genetic diagnosis required more than a diagnostic DNA sequence and included validation with segregation analysis in probands and their families and reverse phenotyping, in which additional testing and specialist consultation are used to identify signs or symptoms not previously recognized, but consistent with, the genetic diagnosis.

A model cost analysis of the entire cohort showed that the workflow saved 20% of cost per patient, suggesting that exome sequencing and early genetic diagnosis can be cost-effective in a carefully selected population with CKD, compared with patients with CKD who have a late genetic diagnosis established after diagnostic odyssey. A real cost analysis on a representative sample of 66 patients randomly selected from all diagnostic referral groups confirmed cost-savings, which averaged 41%. Both cost analyses included expenses for validation of the genetic diagnosis and counseling.

The investigation by Becherucci et al. would be difficult to execute in the United States, since Italy has a national health service. However, Nestor et al.⁹ previously developed a workflow for return of results to a pilot cohort of 104 Columbia University nephrology research recipients who had actionable genetic findings. Using qualitative interviews, they identified challenges associated with returning results to participants and systematically developed workflows to address the challenges. Both the Italian and Columbia University studies demonstrated that clinical implementation of kidney genomic diagnostics is a resource-intensive process. While the need to incorporate genetic tests for hereditary kidney disease into nephrology practice is clear, both studies reveal that test interpretation requires specialized expertise to provide optimal information to the patient and their loved ones for shared decision-making. Models, such as the European Rare Kidney Disease Reference Network, make evidence-based health care for rare kidney diseases in specialized centers accessible through virtual consultation, clinical pathways, and ongoing research.

Venter and Cohen¹⁰ described the 21^st century as the “Century of Biology,” whose onset was marked by human genome sequencing that could provide information to predict and prevent some human diseases. Now, the Century of Biology is intersecting with the American Association of Kidney™ Patients and the European Kidney Health Alliance's Decade of the Kidney to positively affect care for people with kidney diseases. The two Journal of the American Society of Nephrology papers, discussed in this Editorial, highlight that rigorous studies are the pathway to translate the power of human genetics and genomics into benefit for people with kidney diseases.

Disclosures

J.R. Sedor reports consultancy: Boehringer Ingelheim; Research Funding: Calliditas, Goldfinch Bio, Novartis, and Travere for clinical trials; Honoraria: Boehringer Ingelheim; Patents or Royalties: APOL1 transgenic mice licensed to Sanofi Genzyme; Invention disclosure for machine learning analysis of kidney biopsies; Advisory or Leadership Role: Kidney Foundation of Ohio—kidney patient organization for direct aid—Board of Directors, NephCure Kidney International, Chair Kidney X Steering Committee; and Other Interests or Relationships: Editorial Boards—Seminars in Nephrology, Journal of the American Society of Nephrology, American Journal of Nephrology, Glomerular Diseases, ISN—Member.

Author Contributions

J.R. Sedor conceptualized the study and wrote the original draft.