Return Of Genetic Results Research Articles

A New Registry for Genetic Diagnosis of Inborn Errors of Immunity within the Military Health System

Genotypic definition of monogenic inborn errors of immunity (IEIs) continues to accelerate with broader access to next generation sequencing, underscoring this aggregated group of disorders as a major health burden impacting both civilian and military populations. At an estimated prevalence of 1 in 1200 individuals, IEIs affect ~8,000 patients within the Military Health System (MHS). Despite access to targeted gene/exome panels at military treatment facilities, most affected patients never receive a definitive genetic diagnosis that would significantly improve clinical care. To address this gap, we established the first registry of IEI patients within the MHS with the goal of identifying known and novel pathogenic genetic defects to increase diagnosis rates and enhance clinical care. Using the registry, a research protocol was opened in July 2022. Since July we have enrolled 75 IEI patients encompassing a breadth of phenotypes including severe and recurrent infections, bone marrow failure, autoimmunity/autoinflammation, atopic disease, and malignancy. Enrolled patients provide blood and bone marrow samples for whole genome, ultra-deep targeted panel and comprehensive transcriptome sequencing, plus cryopreservation of peripheral blood mononuclear cells for future functional studies. We are also implementing and developing analytical methods for identifying and interrogating non-coding and structural variants. Suspected pathogenic variants are adjudicated by a clinical molecular geneticist using state-of-the-art analysis pipelines. These analyses subsequently inform in vitro experiments to validate causative mutations using cell reporter systems and primary patient cells. Clinical variant validation and return of genetic results are planned with genetic counseling provided. As a proof of principle, this integrated genetic evaluation pipeline revealed a novel, candidate TLR7 nonsense variant in two adolescent brothers who both endured critical COVID-19 pneumonia, requiring mechanical ventilation and extracorporeal membrane oxygenation. Our protocol is therefore poised to greatly enrich clinical genetics resources available in the MHS for IEI patients, contributing to better diagnosis rates, informed family counseling, and targeted treatments that collectively improve the health and readiness of the military community. Moreover, our efforts should yield new mechanistic insights on immune pathogenesis for a broad variety of known and novel IEIs.

EP154: Predictive genomic medicine for thoracic aortic aneurysm and dissection

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition for which the first detectable clinical sign is often a catastrophic event, such as dissection or rupture. TAAD can be the manifestation of a Mendelian disorder and can include additional syndromic features, but these are subtle and difficult to recognize for many clinicians. The detection of a pathogenic variant offers the potential to identify disease in an at-risk individual, but the penetrance of variants associated with TAAD is not certain. We sought to measure the clinical yield of Pathogenic and Likely Pathogenic variants (PLPVs) when identified in a phenotypically unselected population. We evaluated sequence data from a cohort of 3,052 adults who had volunteered for a genome sequencing research study. Individuals were recruited to the cohort through routine healthcare appointments without suspicion of genomic disease. We limited our search to 15 genes with strong evidence of association with syndromic or non-syndromic TAAD, seven of which are on the ACMG v3.0 recommended list for reporting of secondary findings. We assessed all missense and predicted loss of function variants identified by genome sequencing in these 15 genes and applied ACMG standards and guidelines to identify PLPVs. Pathogenicity assessment included manual curation and was not informed by phenotypic data from participants. Individuals who harbored PLPVs were recontacted for targeted reverse phenotyping including diagnostic testing, genetic counseling, and return of genetic results. We identified seven unique PLPVs in our cohort, for a rate of 7/3,052 or 0.23% (95% CI 0.00092 - 0.0047). Among these seven PLPVs, four were found in genes not on the ACMG secondary findings list. None of the participants identified had undergone clinical sequencing outside of the research study and none were previously aware of the molecular finding. Preliminary results from recontact and reverse phenotypic evaluation revealed that three individuals had a personal or family history highly suggestive of a Mendelian form of TAAD, but the option for clinical sequencing had not been addressed by the individuals’ providers. Another individual had a previously suspected connective tissue disorder without clear manifestation of aortic disease. Of the remaining individuals, aspects of their personal or family histories were potentially consistent with a TAAD-associated phenotype. Additional phenotypic evaluation of individuals with PLPVs including cascade testing of family members is ongoing. Our study is the first that we know of to use a strict genome first approach followed by targeted reverse phenotyping to evaluate the clinical yield of TAAD associated PLPVs in a phenotypically unselected population. The process of re-contact and reverse phenotyping highlights the benefits of identifying such variants (even in individuals with a previously known personal or family history of aneurysm). This study pilots predictive genomic medicine for TAAD, and additional research can use a similar framework to assess this approach on a larger scale.

Enhancing the Impact of Genomics Research in Autism through Integration of Research Results into Routine Care Pathways—A Case Series

The return of genetic results (RoR) to participants, enrolled as children, in autism research remains a complex process. Existing recommendations offer limited guidance on the use of genetic research results for clinical care. We highlight current challenges with RoR and illustrate how the use of a guiding framework drawn from existing literature facilitates RoR and the clinical integration of genetic research results. We report a case series (n = 16) involving the return of genetic results to participants in large genomics studies in Autism Spectrum Disorders (ASD). We outline the framework that guided RoR and facilitated integration into clinical care pathways. We highlight specific cases to illustrate challenges that were, or could have been, resolved through this framework. The case series demonstrates the ethical, clinical and practical difficulties of RoR in ASD genomic studies for participants enrolled as children. Challenges were resolved using pre-established framework to guide RoR and incorporate research genetic results into clinical care. We suggest that optimal use of genetic research results relies on their integration into individualized care pathways for participants. We offer a framework that attempts to bridge the gap between research and healthcare in ASD.

Attitudes of Dilated Cardiomyopathy Patients and Investigators Toward Genomic Study Enrollment, Consent Process, and Return of Genetic Results.

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self‐administered surveys examining direct‐to‐participant enrollment and web‐based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web‐based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1‐hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM.

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

PurposeRecruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. MethodsThe costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. ResultsA total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from$579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. ConclusionsAlthough all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Towards precision nephrology: the opportunities and challenges of genomic medicine.

The expansion of genomic medicine is furthering our understanding of many human diseases. This is well illustrated in the field of nephrology, through the characterization, discovery, and growing insight into various renal diseases through use of Next Generation Sequencing (NGS) technologies. This review will provide an overview of the diagnostic opportunities of using genetic testing in the clinical setting by describing notable discoveries regarding inherited forms of renal disease that have advanced the field and by highlighting some of the potential benefits of establishing a molecular diagnosis in a clinical practice. In addition, it will discuss some of the challenges associated with the expansion of genetic testing into the clinical setting, including clinical variant interpretation and return of genetic results.

Family decision maker perspectives on the return of genetic results in biobanking research

PurposeThere are many ethical considerations regarding the return of genetic results to biobanking participants, especially when biobanks collect samples from deceased organ and tissue donors that require the authorization of a family decision maker (FDM). This paper explores FDM knowledge and opinions regarding return of genetic results in the context the Genotype-Tissue Expression (GTEx) Project, which does not return results to participants.MethodsData collection included a survey completed by organ procurement organization (OPO) requesters (n=22) and semi-structured telephone interviews with FDMs (n= 55).ResultsNearly every FDM wanted some form of genetic results returned. Information on treatable diseases (94.3%) and diseases that could affect their children (84.9%) were more desirable than untreatable diseases (71.7%). Sixty percent of FDMs understood that GTEx would not return genetic results. FDMs were 4 times more likely to have correct knowledge of the GTEx policy when their GTEx requester reported discussing the topic with them.ConclusionFDMs from the GTEx project were interested in receiving genetic test results. Marked changes in the infrastructure of GTEx would be required to alter the policy. Regardless, care must be taken to ensure that the return policy is clearly communicated with FDMs in order to dispel misconceptions.

Return of individual genetic results in a high-risk sample: enthusiasm and positive behavioral change.

PurposeThe goal of this study is to examine participant responses to disclosure of genetic results in a minority population at high-risk for depression and anxiety.Methods82 subjects in a genetic study of nicotine dependence were offered personalized genetic results: all were nicotine dependent and 64% self-identified as African American. Pathway Genomics was used to evaluate genetic risks for 5 complex diseases. Participants returned 4–8 weeks following enrollment for in-person genetic counseling interviews and evaluation of baseline measures. A telephone follow-up was performed 4–8 weeks later to assess responses to results.Results50 of the 82 subjects (61%) were interested in receiving genetic results. These participants had multiple risk factors, including high baseline measures of depression (66%) and anxiety (32%), as well as low rates of employment (46%), adequate health literacy (46%), and health insurance (45%). Pathway Genomics reported “increased risk” for at least one disease in 77% of subjects. 95% of participants reported that they appreciated the genetic results, and receiving these results was not associated with changes in symptoms of depression or anxiety. Furthermore, after return of genetic results, smoking cessation attempts increased (p=0.003).ConclusionEven in an underserved population at high-risk for adverse psychological reactions, subjects responded positively to personalized genetic results.

Return of Genetic Results in the Familial Dilated Cardiomyopathy Research Project

The goal of the Familial Dilated Cardiomyopathy (FDC) Research Project, initiated in 1993, has been to identify and characterize FDC genetic cause. All participating individuals have been consented for the return of genetic results, an important but challenging undertaking. Since the inception of the Project we have enrolled 606 probands, and 269 of these had 1670 family members also enrolled. Each subject was evaluated for idiopathic dilated cardiomyopathy (IDC) and pedigrees were categorized as familial or sporadic. The coding regions of 14 genes were resequenced in 311 to 324 probands in five studies. Ninety-two probands were found to carry nonsynonymous rare variants absent in controls, and with Clinical Laboratory Improvement Amendment of 1988 (CLIA) compliant protocols, relevant genetic results were returned to these probands and their consented relatives by study genetic counselors and physicians in 353 letters. In 10 of the 51 families that received results >1year ago, at least 23 individuals underwent CLIA confirmation testing for their family's rare variant. Return of genetic results has been successfully undertaken in the FDC Research Project. This report describes the methods utilized in the process of returning research results. We use this information as a springboard for providing guidance to other genetic research groups and proposing future directions in this arena.