Rare Disease Education Outside of the Classroom and Clinic: Evaluation of the RARE Compassion Program for Undergraduate Medical Students.

Launched in 2014, the RARE Compassion Program is the first international educational program to pair medical students with rare disease patients in order to enhance exposure to and comfort with rare diseases. As part of ongoing quality improvement, this study retrospectively reviewed four years of participant registration data to conduct a program evaluation of the RARE Compassion Program between 2014-2018. During the study period, there were 334 student participants, representing 67.3% of Association of American Medical Colleges (AAMC) member medical schools, and 5389 rare disease volunteers. Despite not requiring in-person interaction, 90.64% of student-volunteer interactions were in-person, while only 5.89% and 3.46% were by video messaging or email correspondence, respectively (p = 0.0002). In a limited post participation survey, 91.7% of students, who matched to 19 out of 27 residency specialities, indicated they would recommend the program to their peers. These findings suggest that the RARE Compassion Program, designed to increase medical student engagement with rare disease patients, has broad appeal. It serves as a novel case study of how extracurricular initiatives supported by non-profit organizations can augment the medical training experience and improve understanding of important and often neglected perspectives.

Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors.

Background: A comprehensive review and description of the clinical features that impact prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is needed. Understanding survival and prognostic features is paramount for clinical advancements and patient care. Methods: PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012 and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumor with at least one measure of survival or progression. Patient-level data were pooled for analyses. This study was prospectively registered in PROSPERO (CRD42021267764) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Twenty-seven studies met the criteria with a total of 135 patients included. Median age at diagnosis was 15.8 years (interquartile range [IQR]: 13.3-22.0) with 90% having localized disease. Co-occurring alterations included ATRX mutation in 93%, TP53 mutation in 88%, and MGMT promoter methylation in 70%. Median time-to-progression was 10.0 months (IQR: 6.0-18.0) and median overall survival was 17.3 months (95% CI: 15.0 to 22.9). The median time from progression to death was 5.0 months (IQR: 3.0-11.7). Factors associated with survival duration were age, as patients ≥18 y/o demonstrated longer survival (hazard ratio [HR] =2.05, 95% CI: 1.16 to 3.62), and degree of upfront resection, as near or gross-total resection demonstrated longer survival compared to those with less than near-total resection (HR = 3.75, 95% CI: 2.11 to 6.62). Conclusion: This systematic review highlights available clinical data for G34-DHG demonstrating poor outcomes and important prognostic features, while serving as a baseline for future research and clinical trials.

A Rare Hemoglobin Variant (ß51Pro†→†His) Causing Misleading Measurements of Hemoglobin A1c.

Glycated hemoglobin A1c (HbA1c) is considered the standard of care for the testing and monitoring of diabetes. Its ability to accurately reflect glycemia, however, is imperfect. Hemoglobin variants-mutant forms of hemoglobin caused by genetic variation present in 7% of the population-are known to adversely affect the ability of HbA1c measurement to reflect glycemic control. We report an illustrative case of a 64-year-old nondiabetic man with a steadily decreasing HbA1c and no symptoms of hypoglycemia or concerning family history. Preliminary investigative workup returned nothing of significance. Genetic sequencing, however, identified a rare benign hemoglobin variant: a heterozygous missense mutation in the gene encoding the hemoglobin ß chain (c.155C > A, p.Pro51His). This variant has been reported only once previously, and the report predates genetic sequence data of the variant. Although this variant had no clinical implications for the patient, it was the cause of falsely low HbA1c levels on high-performance ion-exchange chromatography. This case highlights the importance of considering the effect of hemoglobin variants on the measurement of HbA1c. When available, family history should be carefully considered. Clinicians should suspect hemoglobin variants when HbA1c is too high or low, or discordant with the clinical picture.

Revisiting Risk and Benefit in Early Oncology Trials in the Era of Precision Medicine: A Systematic Review and Meta-Analysis of Phase I Trials of Targeted Single-Agent Anticancer Therapies.

PURPOSE: Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS: We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS: One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION: Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes.

Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation. Qualitative methods were used to explore behavioural and psychosocial consequences of disclosure. ICC genes were analysed in genome sequence data from 7203 research participants; a two-stage approach was used to recruit genotype-blind variant carriers and matched controls. Cardiac-focused medical and family history collection and genetic counselling were followed by standard clinical tests, blinded to genotype. Pathogenic ICC variants were identified in 0.61% of individuals; 20 were eligible for the present study. Four variant carriers and seven non-carrier controls participated. One variant carrier had a family history of ICC and was clinically affected; a second was clinically unaffected and had no relevant family history. One variant, in two unrelated participants, was subsequently reclassified as being of uncertain significance. Analysis of qualitative data highlights participant satisfaction with approach, willingness to follow clinical recommendations, but variable outcomes of relatives' engagement with healthcare services. In conclusion, when offered access to SF, many people choose not to pursue them. For others, disclosure of ICC SF in a specialist setting is valued and of likely clinical utility, and can be expected to identify individuals with, and without a phenotype.

Views of rare disease participants in a UK whole-genome sequencing study towards secondary findings: a qualitative study.

With large-scale genome sequencing initiatives underway, vast amounts of genomic data are being generated. Results-including secondary findings (SF)-are being returned, although policies around generation and management remain inconsistent. In order to inform relevant policy, it is essential that the views of stakeholders be considered-including participants who have made decisions about SF since the wider debate began. We conducted semi-structured interviews with sixteen rare disease patients and parents enroled in genome sequencing to explore views towards SF. Informed by extensive contact with the healthcare system, interviewees demonstrated high levels of understanding of genetic testing and held pragmatic views: many are content not knowing SF. Interviewees expressed trust in the system and healthcare providers, as well as an appreciation of limited resources; acknowledging existing disease burden, many preferred to focus on their primary condition. Many demonstrated an expectation for recontact and assumed the possibility of later access to initially declined SF. In the absence of such an infrastructure, it is important that responsibilities for recontact are delineated, expectations are addressed, and the long-term impact of decisions is made clear during consent. In addition, some interviewees demonstrated fluid views towards SF, and suggestions were made that perceptions may be influenced by family history. Further research into the changing desirability of SF and behavioural impact of disclosure are needed, and the development and introduction of mechanisms to respond to changes in patient views should be considered.

"Not pathogenic until proven otherwise": perspectives of UK clinical genomics professionals toward secondary findings in context of a Genomic Medicine Multidisciplinary Team and the 100,000 Genomes Project.

PurposeApproaches to secondary findings in genome sequencing (GS) are unresolved. In the United Kingdom, GS is now routinely available through the 100,000 Genomes Project, which offers participants feedback of limited secondary findings.MethodsIn Oxford, a Genomic Medicine Multidisciplinary Team (GM-MDT) governs local access to GS, and reviews findings. Semistructured interviews were conducted with 19 GM-MDT members to explore perspectives on secondary findings.ResultsWhile enthusiastic about GS for diagnosing rare disease, members question the rationale for genome screening largely because of lack of evidence for clinical utility and limited justification for use of resources. Members' views are drawn from diverse experiences; they feel a strong sense of responsibility to act in participants' best interests. The capacity to return limited secondary findings should be enabled, but members favor a cautious approach that is responsive to accumulating evidence. Informed participant choice is considered critical, yet challenging. Discrimination of variants is considered essential, and requiring of specialist input and consensus. Multiple areas requiring enhanced engagement and education are identified, i.e., for patients, the public, and health-care professionals; at present, mainstreaming of genomics may be premature.ConclusionUK experts believe that evidence to inform policy toward secondary findings is lacking, arguing for caution.

Expect the unexpected: screening for secondary findings in clinical genomics research.

Background: Due to decreasing cost, and increasing speed and precision, genomic sequencing in research is resulting in the generation of vast amounts of genetic data. The question of how to manage that information has been an area of significant debate. In particular, there has been much discussion around the issue of 'secondary findings' (SF)-findings unrelated to the research that have diagnostic significance. Sources of data: The following includes ethical commentaries, guidelines and policies in respect to large-scale clinical genomics studies. Areas of agreement: Research participant autonomy and their informed consent are paramount-policies around SF must be made clear and participants must have the choice as to which results they wish to receive, if any. Areas of controversy: While many agree that clinically 'actionable' findings should be returned, some question whether they should be actively sought within a research protocol. Growing points: SF present challenges to a growing field; diverse policies around their management have the potential to hinder collaboration and future research. Areas timely for developing research: The impact of returning SF and accurate estimates of their clinical utility are needed to inform future protocol design.

Insights from early experience of a Rare Disease Genomic Medicine Multidisciplinary Team: a qualitative study.

Whole-exome/whole-genome sequencing (WES/WGS) has the potential to enhance genetic diagnosis of rare disease, and is increasingly becoming part of routine clinical care in mainstream medicine. Effective translation will require ongoing efforts in a number of areas including: selection of appropriate patients, provision of effective consent, pre- and post-test genetic counselling, improving variant interpretation algorithms and practices, and management of secondary findings including those found incidentally and those actively sought. Allied to this is the need for an effective education programme for all members of clinical teams involved in care of patients with rare disease, as well as to maintain public confidence in the use of these technologies. We established a Genomic Medicine Multidisciplinary Team (GM-MDT) in 2014 to build on the experiences of earlier successful research-based WES/WGS studies, to address these needs and to review results including pertinent and secondary findings. Here we report on a qualitative study of decision-making in the GM-MDT combined with analysis of semi-structured interviews with GM-MDT members. Study findings show that members appreciate the clinical and scientific diversity of the GM-MDT and value it for education and oversight. To date, discussions have focussed on case selection including the extent and interpretation of clinical and family history information required to establish likely monogenic aetiology and inheritance model. Achieving a balance between effective use of WES/WGS - prioritising cases in a diverse and highly complex patient population where WES/WGS will be tractable - and meeting the recruitment targets of a large project is considered challenging.

Stakeholder views on secondary findings in whole-genome and whole-exome sequencing: a systematic review of quantitative and qualitative studies.

PURPOSE: As whole-exome sequencing (WES) and whole-genome sequencing (WGS) move into routine clinical practice, it is timely to review data that might inform the debate regarding secondary findings (SF) and the development of policies that maximize participant benefit. METHODS: We systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes. RESULTS: Forty-four articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning "actionable" findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients' views were largely influenced by a sense of rights, whereas views of genomics professionals were informed by a sense of professional responsibility. Experience with genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings. CONCLUSION: This review suggests that bidirectional interaction during consent might best facilitate informed decision making about SF and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.Genet Med 19 3, 283-293.

Complete mitochondrial genomes for Icelus spatula, Aspidophoroides olrikii and Leptoclinus maculatus: pan-Arctic marine fishes from Canadian waters.

Three Arctic marine fishes Icelus spatula, Aspidophoroides olrikii and Leptoclinus maculatus have been identified as target species for investigating the effects of ocean warming on population patterns in high-latitude marine habitats around Canada. In preparation for this research, we have resolved whole mitochondrial genome sequences of 16 384, 17 200 and 16 384 bp for each species, respectively. GC content for each species was 47.5%, 44.2% and 45.3%, respectively. Mitogenome gene composition included 13 protein-encoding genes, 2 rRNA and 22 tRNA genes, for I. spatula and L. maculatus, consistent with other teleosts. Only 20 tRNA genes were annotated for A. olrikii, because tRNA-Pro and tRNA-Thr are poorly characterized and aberrantly located in this species.

Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations.

IMPORTANCE: Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions. OBJECTIVE: To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR. DESIGN, SETTING, AND PARTICIPANTS: Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment. EXPOSURES: Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed. MAIN OUTCOMES AND MEASURES: Identification of mutations in KIF11. RESULTS: Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1G>T, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR. CONCLUSIONS AND RELEVANCE: Mutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.

Gyrodactylus laevisoides n. sp. (Monogenea: Gyrodactylidae) infecting northern redbelly dace Phoxinus eos Cope (Cyprinidae) from Nova Scotia, Canada.

Gyrodactylus laevisoides n. sp. is described from the gill rakers of red belly dace, Phoxinus eos Cope (Cyprinidae), from Nova Scotia, Canada. Gyrodactylus laevisoides n. sp. is the second species of Gyrodactylus Nordmann, 1832 described from this host and is characterised by weakly curving hamuli, a small ventral bar lacking anterolateral processes, stout dorsal bar, small marginal hooks with sickles larger proximally than distally and having a small circular process on the heel, a MCO with spines arranged in two arched rows, and lack of obvious excretory bladders. The new species most closely resembles Gyrodactylus laevis Malmberg, 1957, a Eurasian species whose principle host is Phoxinus phoxinus (L.). The two species are separated by Gyrodactylus laevisoides n. sp. having less divergent and longer hamulus root and marginal hook sickle toe with a steeper continuous angle and heel that is less prominent. The morphological description is supplemented with sequences of the 18S gene (449 bp, including the V4 region) and of the ITS region (821 bp). Gyrodactylus sedelnikowi Gvosdev, 1950 infecting Barbatula barbatula (L.) and Gyrodactylus neili Leblanc, Hansen, Burt & Cone, 2006 infecting Esox niger Lesueur are the most genetically similar species on GenBank for the 18S rRNA gene and ITS regions respectively (c.96% and c.92%). Gyrodactylus laevisoides n. sp. belongs to Malmberg's subgenus Gyrodactylus (Gyrodactylus) and phylogenetic analysis of the ITS region groups this species with other members of the subgenus. The phylogeny has two main clades, one comprised of Eurasian species and the other of North American species, specifically Gyrodactylus laevisoides n. sp. and Gyrodactylus neili. It is suspected that this lineage, which is seemingly underrepresented in North America, likely colonised the new world with an ancestral species of Phoxinus via the Bering land connection around the time of the Pliocene.