Milo Rasouly, Hila

Key Points Genetic testing in CKD showed diagnostic and clinical utility in the year following reporting of test results. Genetic testing was helpful for or changed management in 86% of patients with a positive finding and 42% with a negative finding. Clinical utility was seen across 12 clinical cohorts, including CKD of unknown etiology and hypertension or diabetes-related nephropathy. Background CKD is a significant public health burden, affecting >800 million people worldwide with significant cost to the health care system. CKD is a disease process with substantial genetic and phenotypic heterogeneity that can obscure a definitive diagnosis, resulting in suboptimal management. Recent guidelines support greater adoption of genetic testing in CKD. We assessed the diagnostic and clinical utility in the year following broad-panel CKD genetic testing. Methods The Renasight Clinical Application, Review, and Evaluation (RenaCARE) study (NCT05846113) was a single-arm, interventional, prospective, multicenter study evaluating the utility of genetic testing with a 385-gene panel on the diagnosis and management of CKD. Clinical history was collected before testing, and nephrologists responded to questionnaires at both 1 month and 1 year after testing. The impact of genetic testing on CKD diagnosis and management were assessed in active study patients at the 1-year time point. Results In a cohort of 1388 CKD patients with 13 pretest clinical categories of CKD, 335 (24%) patients had a positive genetic finding; 1174 had a questionnaire completed at 1 year and were included in the analysis. Genetic testing was reported helpful for clinical management and/or led to a change in management in 86% of patients with a positive test finding and 42% of patients with a negative test finding. In addition, genetic testing resulted in a change in the physician estimation of the 5-year prognosis for 55% of patients with a positive test finding and 18% of those with a negative test finding. Conclusions Supporting the previous results of the RenaCARE study at 1 month, this report demonstrated that genetic testing was helpful in the clinical management and estimated prognosis of patients with CKD. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT05846113.

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.

Abstract The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network‐3 (eMERGE‐3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE‐3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first‐degree relatives. Across the sites, 279 participants completed a 1‐month and/or 6‐month post‐results survey. By 6 months, only 34% of the 156 respondents shared their results with all first‐degree relatives and 4% did not share with any. Over a third (39%) first‐degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first‐degree relatives compared with 11% of participants who received their results from a non‐genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

AbstractPopulation‐based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life‐altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and “lessons learned” across institutions. A 60‐item survey that consisted of both multiple choice and open‐ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the “real world” of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.