ABSTRACT
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.Copyright © 2023 Elsevier Inc.
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Background/Objectives: The changes and restrictions precipitated by the COVID-19 pandemic have led to innovation in Clinical Genetics service delivery worldwide. At the Guy's and St Thomas' (GSTT) Clinical Genetics Service, telegenetics was implemented at the beginning of the pandemic using the AttendAnywhere videoconferencing platform. We subsequently designed a qualitative study to capture experiences and preferences of Healthcare Professional's (HCP) using this service delivery model. Method(s): We conducted semi-structured interviews with seven HCPs working at the GSTT Clinical Genetics Service, including Genetic Counsellors, Clinical Geneticists and a Clinical Psychologist. Interview content was analysed using a thematic analysis approach. Result(s): We present HCPs' experiences of transitioning between virtual and in-person appointments and their appraisal of the technical and practical aspects of telegenetics. We also present themes that emerged about how HCPs' clinical practice has changed to adapt to telegenetics, as well as differences in both patients' and HCPs' attitudes towards virtual appointments when compared to in-person encounters. Future considerations will be shared regarding the suitability of telegenetics for Clinical Genetics appointments. Conclusion(s): Based on their experience at GSTT, HCPs interviewed would welcome the addition of telegenetics to the Clinical Genetics toolkit beyond the COVID-19 pandemic, and we will provide considerations for future guidelines.
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Video consultations have become a viable alternative for face-to-face consultations during Covid19 pandemic and are expected to be used increasingly in the future. To date, there is little evidence to support the acceptability of these services or to document the benefits and challenges when offering online clinics to HD patients. Method We report on an EHDN WG Genetic Counselling and Testing project of 41 healthcare professionals from 15 European countries. Participants filled in a purposely-designed survey to assess the acceptability, benefits and challenges of telemedicine with HD affected and at risk individuals. The survey was active from March 2020 until March 2021. Results Respondents were geneticists (34%), neurologists (34%), genetic counsellors (15%), and others (psychologists, psychiatrists and research practitioners) (17%). Before the Covid-19 pandemic, professionals saw 4.5 HD patients per week and most (85%) never used telemedicine. During the pandemic, professionals saw 2.4 patients per week in face-toface consultations and 3.4 patients in online consultations. 85% of professionals felt that HD clinics can be done safely and effectively online. Most respondents agreed several aspects of consultations can be done safely online: follow-up counselling (78%), genetic counselling for predictive testing (54%), psychological assessment (49%), psychiatric and behavioural assessment (44%). The main benefits of telemedicine perceived were and challenges were also listed and discussed at length. Conclusions and discussion Our data are encouraging in relation to the potential for virtual and hybrid consultations in HD care. We draw on both quantitative and qualitative data to discuss professionals' views on telemedicine as well as potential implications for future practice.
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Introduction - The COVID 19 pandemic led to restrictions on the conventional ways of healthcare delivery. Telemedicine provided a viable solution that was in line with the social distancing policies imposed to minimize disease transmission. This demanded physicians adapt to new ways of healthcare delivery. We surveyed geneticists across the country to determine their experience and to ascertain if telegenetics will be a lasting change. Materials and Methods - A 23 item standardized survey was distributed to various US-based geneticists via email and other social media platforms focusing on their experience of providing care via telemedicine. Results - We received 69 responses from physicians across 26 states. Of these, 91% practiced in academia. 70% responded that pediatric genetics takes up more than 50% of their practice. 68% had over 50% of their practice switch to telemedicine. 77% felt they could provide adequate care via telemedicine and 94% of providers would like to continue telemedicine post-pandemic. Conclusion - The future of telemedicine looks promising as the majority of clinicians would like to routinely use telemedicine post-pandemic. Uniform guidelines for use of telemedicine in genetics may need to be proposed by professional societies and supported by federal laws.
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Purpose/Objectives: 1. Describe the clinical trial consideration process from family point of view, so parents know the questions to ask and providers can support them 2. Place consideration in context of life with a child having a rare disease/disorder, to prepare both parties for what lies ahead 3. Illustrate variety of decisions and outcomes that families experience, to emphasize that there is no one right answer Design/Methods: The project is a digital library (unit) of content presented in a variety of media (video, downloadable guide, podcast, blog) and organized around subjects of greatest potential concern and interest to families and providers based on the described experience of families who considered and/or enrolled in a clinical trial. Unit is available online, free, 24/7. Results: The Evaluating the Clinical Trial Option unit was introduced in February 2020. In 12 months, there were 9,640 video views, the guides were viewed 226 times, and the Guided Pathway visited 356 times. (numbers would be updated for the poster). Staff has presented its content to numerous gatherings of providers, patient disease groups, and industry professionals to overwhelmingly positive feedback. Professionals serving the rare disease community, especially patient advocates at biotech companies and patient disease groups, have reached out to CPN for resources from the unit to meet particular needs: e.g. content about informed consent helped a family understand the restrictions around posting to social media and content about inclusion criteria -- including a parent's hope to 'train' towards meeting the criteria, as well as the potential for parents to feel they have failed if their child does not meet that criteria -- helped a parent navigate their stress and worry about COVID-induced disruptions to their child's physical therapy prior to seeking participation in a trial. Companies have reported valuing the unit as a therapy- and industry-neutral, unbiased source of information for families. Companies link to it in their patient support portals and use the videos for in-service training. The patient disease group NTSAD, anticipating multiple clinical trials for its affected families, links to the unit on its website and sends families considering enrollment links to it in email communications. The American Society of Gene and Cell Therapy has recognized the unit for covering the emotional aspects of trial participation that are not covered in their resources and has embedded links to it in their patient- and provider-facing websites. Conclusion/Discussion: The unit was designed as a resource to share with families and for their self-service, but grows in momentum and impact as it is used as a resource for educating colleagues -- including genetic counselors, medical geneticists, doctors working with rare disease patients - and peers striving to better understand the lived family experience.
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Background: The Familial Mediterranean Fever (FMF) Program at the University of California, Los Angeles is the only dedicated FMF diagnostic and treatment clinic in the United States, receiving global referrals. FMF is a rare autosomal recessive genetic disorder characterized by recurrent febrile polyserositis. Serious complications from untreated FMF are easily preventable with early diagnosis and treatment. The COVID-19 pandemic constrained educational and interdisciplinary in-person visits and prompted exploration of innovative telehealth solutions. Objective: This study aimed to explore the feasibility and clinical process outcomes associated with a multidisciplinary telemedicine model to deliver consultative and continuing care to FMF patients. Our secondary objectives included assessing provider, patient, and trainee satisfaction. Study design: We implemented a multidisciplinary telemedicine clinic with gastroenterologists, a medical geneticist, and trainees. All patients with suspected FMF referred to our clinic during the pandemic were included. Patients were sent a HIPAAcompliant Zoom link for their clinic appointment. We mirrored our in-person academic teaching model, first with the trainee interviewing the patient virtually and then later presenting to the team, along with family members, who joined for the case presentation and consensus on diagnostic impressions and management recommendations. Patient characteristics and clinical process outcomes were assessed during the visit and from the electronic medical record (EMR). Post-visit surveys of patients, physicians and trainees were then taken to assess effectiveness and desirability of the approach. Results: 86 patients were enrolled in the multidisciplinary telemedicine model from March 2020 to March 2021. In comparison, 87 pre-pandemic visits occurred between March 2019 to March 2020. No significant difference was found in patient volume seen with telehealth and surveys showed increased provider, patient, and trainee satisfaction. The telehealth model enabled health care delivery to a variety of locations that lacked expert experience with this rare disease. Patients could also avoid costly travel to UCLA and risk exposure to COVID-19. Surveys showed increased satisfaction with Zoom than the integrated video functionality in our in-house EMR by allowing for inclusion of multiple specialists and interested family members. Sample collection for indicated laboratory tests could still be ordered at a local phlebotomy center. Conclusion: A multidisciplinary telemedicine model for outpatient management of FMF patients resulted in rates of ambulatory management similar to those seen pre-pandemic and resulted in improved patient and physician satisfaction. FMF is especially amendable to this approach, as patients are asymptomatic between attacks, making hands-on physical exam less pertinent.
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Previous studies of genome sequencing (GS) in critically ill childrenhave made use of either modified hardware or working procedureswhich would be difficult, if not impossible, to integrate into existingclinical workflows1. Our lab’s transition from exome sequencing (ES) to GS offered an opportunity to implement in-house rapid genomesequencing (rGS) in critically ill children in a manner which couldintegrate with existing clinical workflows. We conducted a feasibilityand implementation pilot by offering rGS to child-parent triosconcurrently undergoing clinical rapid ES (rES) via a reference lab.The purpose of this study was to identify and address operationalbarriers to implementation of a rGS program capable of communicatinga preliminary result within 7 days of consent. We consideredthis time span to be more reflective of clinical realities than lab-quotedturnaround times (TAT) which typically start at sample receipt andthus do not account for challenges in sample acquisition and pre-testcounseling in a critical care setting, nor the impact of shipping times.Here we present data on TAT and lessons learned from the first 27subjects enrolled.Using rapid cycle improvement methodologies, we identified fourdistinct but inter-related workflows requiring optimization:1. Pre-analytic: patient identification through acquisition ofsamples2. Wet-lab: extraction through sequencing3. Bioinformatics: secondary and tertiary analysis as well as rapididentification of causal variants4. Return of resultsFigure 1 summarizes TAT across cases, demonstrating the markedimprovements in TAT with our programmatic approach to improvement.We used our first 9 cases to determine a baseline TAT for theentire process and to delineate the 4 main workflows (above). Atbaseline, excluding cases delayed by COVID-19 restrictions, mean TATwas 17.12 days (3 sequential deviant range: 7.05–27.19 days).Following deployment of our programmatic approach to rGS, meanTAT fell to 6.19 days (3 sequential deviant range: 0.51–11.87 days).Table 1 summarizes the observations and insights, by workflow, whichimpacted upon TAT and/or implementation. The single biggest impacton TAT was optimization of bioinformatics by removing all manualsteps between starting sequencing and producing human interpretable,filtered, annotated output of high-priority variants for interpretation.The second biggest source of improvement was optimization ofthe sequencing itself as well as prioritizing sample processing for andaccess to sequencing runs. While variant ranking is helpful in identifying causal variants, in 9/10 cases with a diagnostic findingthe causal variant(s)were obvious to the study teamwithin minutes ofviewing the annotated variant list, regardless of variant rank. (Figure Presented) As time required for sequencing and analytic workflows fell, therelative contribution of other workflows to overall TAT shifted and itbecame more obvious that early identification and utilization of thisapproach is very important in lowering overall time to diagnosis(Figure 2). In 6/10 cases with a diagnostic finding, the initial approachof the clinical team was NOT rES (and thus patients were not eligiblefor rGS on a research basis). Had rGS been the initial diagnosticmodality chosen, a diagnosis could have been reached in a median 12days sooner (range 2–28 days). There were also several cases wheresequencing was delayed when one or both parents did not present tothe lab to provide a blood sample in a timely manner. Optimization ofsequencing or analytic workflows cannot meaningfully improveoutcomes either of these situations.Our findings suggest some important considerations for institutionsdeveloping or seeking to improve rapid sequencing programs for acuteand critically ill children: (Table Presented) • Optimization of computational resource utilization and phenotypecuration saves more time than improved variant filtering orprioritization.• Obtaining samples from parents is non-trivial.• Even trained geneticists may fail to recognize appropriatecandidates for rGS.
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Integration of genomics into health practice depends on successful implementation in non-research settings. We describe a medical home-centered implementation at the intersection of genomic medicine and population health in the UVM Health Network. In this clinical implementation, the hospital laboratory orchestrates a collaboration involving primary care providers (PCPs), patient and family advisors, health system administrators, clinical genetics services, oncologists and cardiologists, Vermont’s accountable care organization, and a commercial CLIA genomic testing laboratory. Phenotypically unselected adult primary care patients are offered “The Genomic DNATest” at no cost as part of their regular care. Testing is introduced by primary care providers and their staff using a brief animated video and printed decision aids with graded detail. Question resolution and pre- and post-test genetic counseling is offered at no cost using telephone, video, or in-person visits, and is coordinated bya single phone and email contact point, the Genomic Medicine Resource Center. 431 genes are sequenced for germline health risk and recessive carrier variants;only pathogenic and likely-pathogenic variants are reported. New reports are issued when reported and unreported variants are later reclassified. Test reports are reviewed by a clinical geneticist and genetic counselor. Two brief "action plans" are developed with PCP and patient focus in a single messaging document. This is prepended to the lab reports before release to the PCP, who reviews and then conveys them to the patient. PCPs and their staff receive initial training on the test and process and are invited to participate in an online community with monthly video case discussions. Among the first 72 patients tested, 17% had a health risk identified. This included dominantly inherited disorders and bi-allelic or hemizygous variants for common recessive disorders. Care pathways created in advance using multi-disciplinary expertise were activated for those. Free testing for blood relatives was made available. 76% of tested patients had at least one heterozygous recessive disease variant identified, and low-cost partner testingwas made available. Frequency of positive test results was in line with population frequency predictions. Pre- and post-test genetic counseling uptakewas lower than expected. This raised the question of unmet informational needs. A 2-page anonymous process quality survey mailed twice to the first 61 tested patients had a 31% return rate. Key findings included (1) pre-test engagement methods and decision aids were helpful;(2) the testing decision was influenced equally by value for the individual’s health, for their family’s health, and for researchers;(3) emotions during the ∼4-week time to results were neutral or excited, with none experiencing anxious feelings, and none reported the wait time as too long;(4) 21% reported contacting the Genomic Medicine Resource Center;(5) 16% reported referral to a specialist due to their result;(6) about half reported sharing the results with family members, but none reported any family members getting tested;(7) none indicated they were dissatisfied with the testing and result process, and only one responded they would not recommend others get the test;and (8) all agreed or somewhat agreed that the PCPs officewas the right place to do this testing.While this implementation was designed with scalability and a low management profile in mind, several systems-level barriers were encountered that contributed to lower engagement efforts and slower expansion than planned. This included lack of institutional information technology resources to surmount paper-based systems for requisitions, sample-routing, and consent forms;dependency of the patient engagement process during PCP visits on rooming and nursing staff during times of staffing shortages;susceptibility to practice model disruptions and priorities caused by the Covid-19 pandemic;and PCP time distraction resulting from user interface and polic changes in our EHR during the pilot. These barriers are targets for study and continuous process improvement activities. In summary, an example of clinical genomic population health testing using a medical-home focus has been successfully implemented in a non-research setting, supported by multi-disciplinary collaboration. This implementation depends on minimal staff, avoids financial barriers to access and genetic counseling, and offers a short, defined, test turnaround time as compared to similar biobank-based research programs. Tested patients find the program satisfactory, and meaningful test results are at least as common as in existing population health risk screening archetypes.
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Introduction: The COVID-19 pandemic has led to rapid changes in the delivery of medical care across the country. Telemedicine has been widely adopted by several different medical specialties including genomic practices. Methods: We surveyed medical geneticists in training and practice to investigate their experience with the implementation and use of telemedicine across the country. This was an IRB exempt study. A standardized questioner was used. A 23-item survey was distributed around the United States through email. It included questions on implementation of telehealth in the outpatient setting, its impact on care delivery and provider experience during this time. The survey was anonymous and we received 69 responses. Results: 69 geneticists from 27 states responded. 91% were in academic practice. 67% were in independent practice with a median of 11 years in practice. 68% of them had over 50% of their practice switch to Telehealth during the time of COVID19 pandemic. Most were made aware of billing changes (84%), had tech support from their institution (87%) and had adequate access to PEE (94%) while in clinic. 70% of them saw pediatric patients greater than 50% of their clinical time. Majority reported that parents did not know that the child had to be present for the telemedicine visit (79%). 77% felt they could provide good care during the television while 51% felt that examination was rather limited. There was a change in testing paradigm as well. Most providers are sending DNA kits to patients home (94.2%) and 60% have not seen any increase in result turnaround time. 94% providers would like to continue telemedicine after the pandemic ends. Only 11% of providers in academic practice had their academic expectations change while working in a pandemic.Conclusion: Genetics Providers across geographic areas have rapidly incorporated Telehealth into their practices. This is much like many other nonsurgical practices. Results from our survey demonstrate that most providers feel the care they provide over tele health is adequate and would like to keep at least some part of their practice as virtual after the pandemic. Mailing testing kits to patients home has become widely accepted and does not seem to have increased tur around time for most practices. Patient education about the expectations during tele visit can be improved. Review of the referral process to triage which patients would benefit from an inperson exam vs televisit could be considered in the future
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Objectives: To understand the pathways by which European patients with X-linked retinitis pigmentosa (XLRP) arrive at retina specialists (RS) and geneticists for diagnosis, and the impact of COVID-19 on patient management. Methods: The EXPLORE XLRP 1 survey interviewed RS (n=20) and geneticists (n=5) in France, Germany, Italy, Spain, and the United Kingdom (UK) to record information about healthcare pathways and diagnostic approaches for patients with XLRP (n=80). Results: Patients (mostly male [91%] and aged 18–40 years [57%]) experienced an average time of 4 years between XLRP symptoms and diagnosis. In France, Spain, and Italy, patient pathways are linear: most patients see RS/geneticists by ophthalmologist referral. In Germany and the UK, patients see RS/geneticists through multiple routes, also including general practitioner and optometrist referrals. Genetic testing was used as part of XLRP diagnosis in 78% of patients. Genetic testing usually took >6 weeks to receive results, and some patients waited up to 6 months. Genetic testing was fully reimbursed for most patients, except those in Spain, where patients largely incurred the full cost. In the UK, testing costs were co-paid by 14% of patients. Despite barriers to genetic testing (e.g., costs, long waiting times for results), physicians agreed that genotypic diagnosis is helpful to predict disease progression and to enable patient involvement in clinical trials. The COVID-19 pandemic reduced the frequency of in-person clinic visits, but some physicians utilized tele-consultation and remote patient management. Conclusions: The pathways by which patients with XLRP in Europe visit RS and geneticists are complex, lengthy, and vary considerably by country. This survey reported high usage of genetic testing to confirm XLRP diagnosis, but long waiting times for test results accounts for incomplete uptake, especially among older patients. Tele-consultations and remote management have emerged as potential solutions for monitoring patients during the COVID-19 pandemic.