Developing a genetic testing panel for evaluation of morbidities in kidney transplant recipients.

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.

The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.

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.

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease.

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 .

Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies.

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 ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to ∼40% 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.

Genetic evaluation of living kidney donor candidates: A review and recommendations for best practices.

The growing accessibility and falling costs of genetic sequencing techniques has expanded the utilization of genetic testing in clinical practice. For living kidney donation, genetic evaluation has been increasingly used to identify genetic kidney disease in potential candidates, especially in those of younger ages. However, genetic testing on asymptomatic living kidney donors remains fraught with many challenges and uncertainties. Not all transplant practitioners are aware of the limitations of genetic testing, are comfortable with selecting testing methods, comprehending test results, or providing counsel, and many do not have access to a renal genetic counselor or a clinical geneticist. Although genetic testing can be a valuable tool in living kidney donor evaluation, its overall benefit in donor evaluation has not been demonstrated and it can also lead to confusion, inappropriate donor exclusion, or misleading reassurance. Until more published data become available, this practice resource should provide guidance for centers and transplant practitioners on the responsible use of genetic testing in the evaluation of living kidney donor candidates.

The effect of genetic education on the referral of patients to genetic evaluation: Findings from a national survey of nephrologists.

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.

Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes.

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.

ZEB2 controls kidney stromal progenitor differentiation and inhibits abnormal myofibroblast expansion and kidney fibrosis.

FOXD1+ cell-derived stromal cells give rise to pericytes and fibroblasts that support the kidney vasculature and interstitium but are also major precursors of myofibroblasts. ZEB2 is a SMAD-interacting transcription factor that is expressed in developing kidney stromal progenitors. Here we show that Zeb2 is essential for normal FOXD1+ stromal progenitor development. Specific conditional knockout of mouse Zeb2 in FOXD1+ stromal progenitors (Zeb2 cKO) leads to abnormal interstitial stromal cell development, differentiation, and kidney fibrosis. Immunofluorescent staining analyses revealed abnormal expression of interstitial stromal cell markers MEIS1/2/3, CDKN1C, and CSPG4 (NG2) in newborn and 3-week-old Zeb2-cKO mouse kidneys. Zeb2-deficient FOXD1+ stromal progenitors also took on a myofibroblast fate that led to kidney fibrosis and kidney failure. Cell marker studies further confirmed that these myofibroblasts expressed pericyte and resident fibroblast markers, including PDGFRß, CSPG4, desmin, GLI1, and NT5E. Notably, increased interstitial collagen deposition associated with loss of Zeb2 in FOXD1+ stromal progenitors was accompanied by increased expression of activated SMAD1/5/8, SMAD2/3, SMAD4, and AXIN2. Thus, our study identifies a key role of ZEB2 in maintaining the cell fate of FOXD1+ stromal progenitors during kidney development, whereas loss of ZEB2 leads to differentiation of FOXD1+ stromal progenitors into myofibroblasts and kidney fibrosis.

Genetics of Kidney Disease: The Unexpected Role of Rare Disorders.

Hundreds of different genetic causes of chronic kidney disease are now recognized, and while individually rare, taken together they are significant contributors to both adult and pediatric diseases. Traditional genetics approaches relied heavily on the identification of large families with multiple affected members and have been fundamental to the identification of genetic kidney diseases. With the increased utilization of massively parallel sequencing and improvements to genotype imputation, we can analyze rare variants in large cohorts of unrelated individuals, leading to personalized care for patients and significant research advancements. This review evaluates the contribution of rare disorders to patient care and the study of genetic kidney diseases and highlights key advancements that utilize new techniques to improve our ability to identify new gene-disease associations.

Incorporating genetics services into adult kidney disease care.

Studies have shown that as many as 1 in 10 adults with chronic kidney disease has a monogenic form of disease. However, genetic services in adult nephrology are limited. An adult Kidney Genetics Clinic was established within the nephrology division at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Between June 2019 and December 2021, a total of 363 patients were referred to the adult Kidney Genetics Clinic. Of those who completed genetic testing, a positive diagnostic finding was identified in 27.1%, a candidate diagnostic finding was identified in 6.7% of patients, and a nondiagnostic positive finding was identified in an additional 8.6% of patients, resulting in an overall yield of 42.4% for clinically relevant genetic findings in tested patients. A genetic diagnosis had implications for medical management, family member testing, and eligibility for clinical trials. With the utilization of telemedicine, genetic services reached a diverse geographic and patient population. Genetic education efforts were integral to the clinic's success, as they increased visibility and helped providers identify appropriate referrals. Ongoing access to genomic services will remain a fundamental component of patient care in adults with kidney disease.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

Diagnostic sequencing to support genetically stratified medicine in a tertiary care setting.

PURPOSE: The goal of stratified medicine is to identify subgroups of patients with similar disease mechanisms and specific responses to treatments. To prepare for stratified clinical trials, genome-wide genetic analysis should occur across clinical areas to identify undiagnosed genetic diseases and new genetic causes of disease. METHODS: To advance genetically stratified medicine, we have developed and implemented broad exome sequencing infrastructure and research protocols at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital. RESULTS: We enrolled 4889 adult and pediatric probands and identified a primary result in 572 probands. The cohort was phenotypically and demographically heterogeneous because enrollment occurred across multiple specialty clinics (eg, epilepsy, nephrology, fetal anomaly). New gene-disease associations and phenotypic expansions were discovered across clinical specialties. CONCLUSION: Our study processes have enabled the enrollment and exome sequencing/analysis of a phenotypically and demographically diverse cohort of patients within 1 tertiary care medical center. Because all genomic data are stored centrally with permission for longitudinal access to the electronic medical record, subjects can be recontacted with updated genetic diagnoses or for participation in future genotype-based clinical trials. This infrastructure has allowed for the promotion of genetically stratified clinical trial readiness within the Columbia University Irving Medical Center/NewYork-Presbyterian Hospital health care system.

Do research participants share genomic screening results with family members?

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.

Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.

BACKGROUND: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown. METHODS: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2. RESULTS: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected. CONCLUSIONS: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

An electronic health record (EHR) log analysis shows limited clinician engagement with unsolicited genetic test results.

How clinicians utilize medically actionable genomic information, displayed in the electronic health record (EHR), in medical decision-making remains unknown. Participating sites of the Electronic Medical Records and Genomics (eMERGE) Network have invested resources into EHR integration efforts to enable the display of genetic testing data across heterogeneous EHR systems. To assess clinicians' engagement with unsolicited EHR-integrated genetic test results of eMERGE participants within a large tertiary care academic medical center, we analyzed automatically generated EHR access log data. We found that clinicians viewed only 1% of all the eMERGE genetic test results integrated in the EHR. Using a cluster analysis, we also identified different user traits associated with varying degrees of engagement with the EHR-integrated genomic data. These data contribute important empirical knowledge about clinicians limited and brief engagements with unsolicited EHR-integrated genetic test results of eMERGE participants. Appreciation for user-specific roles provide additional context for why certain users were more or less engaged with the unsolicited results. This study highlights opportunities to use EHR log data as a performance metric to more precisely inform ongoing EHR-integration efforts and decisions about the allocation of informatics resources in genomic research.

Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient.

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.

Returning negative results from large-scale genomic screening: Experiences from the eMERGE III network.

Population-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.

GeneLiFT: A novel test to facilitate rapid screening of genetic literacy in a diverse population undergoing genetic testing.

With the broader introduction of genomic medicine in research and clinical care, an increasing number of persons are offered genetic testing. Many factors, including genetic literacy, may impact the utilization of genetic results by patients and their families. We developed a rapid, self-administered measure of genetic literacy, called Genetic Literacy Fast Test (GeneLiFT). We next evaluated the association of GeneLiFT scores with the comprehension of limitations of genomic medicine in participants undergoing genetic testing in the NIH-sponsored eMERGE III study at Columbia University Irving Medical Center, New York. All participants underwent genetic screening for variants in 74 actionable genes associated with adult-onset disorders. A diverse cohort of 724 participants completed the survey (60% women, 45% less than 40 years old, and 53% self-reported White non-Hispanic ancestry). The GeneLiFT was validated using known group differences based on education, health literacy, and numeracy, and with questions assessing genetic knowledge. GeneLiFT identified multiple standard genetics terms, that is, jargon, not recognized by more than 50% of participants (including actionability and pathogenicity). Low genetic literacy, identified in 210 participants (29%), was significantly associated with poor understanding of the limitations of genetic testing (p-values < 10-9 ). This association was independent of education, health literacy, and numeracy levels, highlighting the importance of directly measuring genetic literacy. Low genetic literacy was also associated with low satisfaction with the informed consent process. GeneLiFT is a practical tool for rapid assessment of genetic literacy in large studies or clinical care. GeneLiFT will allow future research to efficiently assess the role of genetic literacy on the clinical impact of genetic testing.

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

Ethical conflicts in translational genetic research: lessons learned from the eMERGE-III experience.

PURPOSE: The Electronic Medical Records and Genomics (eMERGE) Consortium integrated biorepository-based research with electronic health records (EHR) to return results from large-scale genetic tests to participants and uploaded those data into the EHR. This article explores the ethical issues investigators encountered in that process. METHODS: We conducted in-depth, semistructured interviews with study personnel of the eMERGE-III Consortium sites that returned results. RESULTS: We discuss major ethical issues that arose while attempting to return research results from the eMERGE Consortium to individual participants. These included difficulties recontacting those participants who had not explicitly consented to such and disclosing results to many participants with insufficient infrastructure and staff. Investigators reported being driven by a supererogatory clinical impulse. CONCLUSION: All these issues ultimately derive from ethical conflicts inherent to translational work being done at the interface of research and clinical care. A critical rethinking of this divide is important, but infrastructural support for such work is necessary for an ethically sound rollout of large-scale genetic testing.