Robert D. Steiner

Background: Accurate descriptions of human genomic variants are crucial for gene-disease association, discovery, and clinical diagnosis. Although standardized genomic nomenclature, expertly curated and promulgated by the Human Genome Variation Society and the International Standing Committee on Human Cytogenomic Nomenclature, is strongly encouraged in scientific publications, many journals lack systematic mechanisms to ensure compliance with these nomenclature standards. Methods: Genetics in Medicine developed detailed author instructions for gene/variant nomenclature and a protocol for scientific editorial teams, which promote adherence to gene/variant nomenclature standards in published works. We present results from a systematic review of manuscripts submitted over a 2-year period, applying a standardized rubric and severity scoring system based on this protocol. In addition, we assessed how erroneous variant nomenclature published in 4 different manuscripts affects findability using 3 open-source tools. Results: Of submitted manuscripts, 100% demonstrated noncompliance with current nomenclature standards. Furthermore, every manuscript contained one or more errors expected to significantly reduce the probability of variant findability during routine database searches and/or variant curation efforts. Findability was complicated by differences inherent to each database or search engine’s structure, resulting in an additional layer of variability in the literature returns. Conclusions: We conclude that strict adherence to gene/variant nomenclature standards is critical in published works, and that rigorous author instructions are insufficient to ensure adherence to nomenclature standards. In addition, we share strategies for the implementation of technical, nomenclature-focused editing within a journal’s editorial framework to promote improved genomic variant findability.

Over 90% of missense variants across ∼4,000 disease-associated genes are variants of uncertain significance (VUS). Experimental variant effect measurements provide critical evidence about pathogenicity and inform disease biology, but most variants lack data and clinical translation has been limited. The Impact of Genomic Variation on Function Consortium generated experimental data for 62,215 variants across ten genes using multiplexed assays and 1,407 variants across 163 genes using arrayed assays, curated 193,139 additional community-generated variant effect measurements across 30 additional genes, and developed automated calibration methods for translating experimental data and variant effect predictions into clinical evidence. To reduce current VUS, we developed a scalable workflow using only experimental and predictive evidence, enabling reclassification of 75% of the 16,115 VUS in these genes as pathogenic or benign with 90,000 unobserved variants; 62% had enough evidence to be “preclassified” as pathogenic or benign. We validated our data, evidence and classifications using All of Us and created interactive resources to enable clinical use of the calibrated data. Thus, for 40 genes, representing 1% of the clinical genome, we resolve most existing VUS and future variants, illustrating how systematic use of scalable evidence can empower genomic medicine.

The great majority of human monogenic, single protein deficiency disease patients, who comprise ~ 0.5% of the population, are incurable. When available, Enzyme Replacement Therapy (ERT) is current state-of-the art therapy for the vast majority of the subset of these diseases caused by enzyme deficiencies. For example, Fabry disease, caused by hemizygous- or heterozygous-pathogenic variants in GLA encoding human-galactocersbrosidase-α (hGLA), is a rare, single protein-deficiency disease. Fabry patients require intravenous-administration of hGLA Enzyme Replacement Therapy (ERT) every two-weeks for-life. ERT costs ~ $300,000 per-year and can cause frequent infusion reactions, which can be life-threatening. The very-high yearly GLA ERT costs, as well as the recurrent, life-threatening hGLA IV infusion-reactions experienced by some patients, can cause them to permanently-discontinue ERT. This can accelerate Fabry-disease progression, leading to premature-death. Therefore, new, more effective-, safe-, durable-, cost-effective, single deficient-protein replacement platforms are urgently-needed to more-effectively treat a wide-spectrum of these rare, monogenic single protein deficiency diseases. Here we demonstrate that one intravenous-administration of our 1 ^st -generation HEDGES DNA-vector encoding wildtype-hGLA (T ¹ / ₂ < 20-minutes) produced hGLA serum-protein levels in the normal human 1,000-10,000 pg/ml range for only < 14 days. We then-created our 2 ^nd -generation HEDGES hGLA DNA-vector. One intravenous-administration of this DNA-vector produced durable (>550 days) serum hGLA serum levels in the 1–10 ng/ml, thus increasing the duration of hGLA serum-protein levels produced by > 38,100 fold versus administering bioreactor-produced, wildtype hGLA-protein. We also showed one intravenous-administration of our 1 ^st -generation HEDGES DNA-vector encoding the wildtype human growth hormone (hGH) protein, (T ¹ / ₂ < 20-minutes), produced serum hGH levels in the 1–10 ng/ml for > 330 days, thus increasing the duration of hGLA serum-protein levels by > 22,860 fold versus administering wildtype hGH-protein. Last, one intravenous-administration of our 2 ^nd -generation HEDGES hGLA DNA-vector produced serum hGLA levels in the normal human 1–10 ng/ml range for > 160 days in GLA knockout-mice, a 2,800-fold increase versus wildtype hGLA-protein. hGLA-ERT produces major therapeutic-responses in GLA knockout-mice. These substantial ERT-responses in GLA knockout-mice have been shown to be accurately-recapitulated in Fabry patients. Thus, Fabry disease appears a promising-target for subsequent phase-1 HEDGES-based human clinical trials.

Objective: To describe the disease burden in patients with Pompe disease treated with enzyme replacement therapy (ERT) in the US as defined by comorbid conditions, supportive services, and treatment patterns. Methods: A retrospective cohort study (01/01/2012–09/30/2022) was conducted using the Merative™ MarketScan Research Databases. Inclusion criteria were: ≥ 2 outpatient or ≥1 inpatient claims of Pompe disease, ≥ 1 claim of ERT, and continuous enrollment in medical/prescription coverage for ≥90 days before diagnosis date for patients ≥2 years and ≥1-month post-index date. Patients were stratified into infantile-onset Pompe disease (IOPD) or late-onset Pompe disease (LOPD) cohorts based on age at diagnosis and clinical presentation. Key comorbidities, supportive services, and treatment modifications were presented as cumulative incidence. Results: A total of 105 patients were included (IOPD: n = 50; LOPD: n = 55). For IOPD and LOPD groups, the 12-month cumulative incidence was 84.5% and 79.4% for respiratory, 57.4% and 54.3% for ambulatory, 67.8% and 33.4% for gastrointestinal, and 16.9% and 28.7% for cardiovascular comorbidities, respectively; 12-month cumulative incidence was 66.9% and 31.8% for physical therapy, 59.5% and 3.9% for speech therapy, 48.6% and 1.8% for immune tolerance induction or intravenous immunoglobulin, 47.3% and 11.2% for nutritional therapy, 15.1% and 17.0% for respiratory support, 27.8% and 3.7% for occupational therapy, and 8.3% and 11.1% for ambulatory support, respectively. Fourteen (IOPD: n = 2; LOPD: n = 12) patients switched ERT therapy, and 21 (IOPD: n = 14; LOPD: n = 7) had ≥1 dose modification. Conclusions: Patients with Pompe disease demonstrate substantial comorbidity burden and utilization of supportive services despite ERT treatment.

Global Heart is the official and primary publication of the World Heart Federation, offering a platform for the dissemination of knowledge on research, developments, trends, solutions and public health programmes in the area of cardiovascular disease. Global Heart welcomes research results, points of view and educational material on the prevention, treatment and control of cardiovascular disease with a special focus on low and middle-income countries which are facing the brunt of epidemiological transition.Global Heart strongly encourages authors to adhere to CONSORT, STROBE, STARD, and PRISMA guidelines for reporting of clinical trials, observational studies, diagnostic test accuracy papers, and systematic reviews or meta-analyses. Authors are required for submission to download and complete the appropriate Equator Network checklist: http://www.equator-network.org/.

Aims: Urea cycle disorders (UCDs) can cause ammonia accumulation and central nervous system toxicity. Nitrogen-binding medications can be efficacious but certain attributes may negatively impact adherence. This study sought to quantify the administration-related attributes influencing overall prescription selection and patient adherence.Methods: A web-based, quantitative survey including discrete choice experiment (DCE) methodology captured responses from health care providers for patients with UCDs. A series of hypothetical treatment profile sets with attributes such as route of administration, taste/odor, preparation instructions, packaging, dose measurement, and weight use restrictions were presented. From 16 sets of 3 hypothetical product profiles, respondents evaluated attributes most preferred for prescription selection or patient adherence. Attributes assumed a higher overall preference if relative importance (RI) scores were >16.67% (the value if all attributes were of equal importance). Preference weight scores were assessed. A nine-point Likert scale assessed respondent attitudes, such as satisfaction.Results: A total of 51 respondents completed the survey. Respondents reported dissatisfaction with current treatments (mean [SD] = 5.4 [1.7]). For prescription selection, four attributes achieved RI >16.67%: taste/odor (24%), weight restrictions (21%), preparation instructions (18%), and route of administration (17%). For adherence, three attributes related to administration achieved RI >16.67%: taste/odor (28%), preparation instructions (21%), and route of administration (17%). Preference weights for "taste/odor masked" were higher than "not taste/odor masked" for prescription selection (mean [SD]; 1.52 [1.10] vs -1.52 [1.10]) and treatment adherence (73.8 [55.2] vs -73.8 [55.2]).Limitations: This study contained a relatively small sample size. Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases.Conclusions: Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs.