Rare Disease Research Research Articles

GeNepher data- and biobank for patients with (suspected) genetic kidney disease: Rationale, design and status update

BackgroundClinical research on monogenic kidney disease (MKD) is thriving and the need for large cohorts, prospective data collection and biobanking is increasing. We aim to create a sustainable large MKD biobank with a vast amount of uniformly collected high-quality data that is readily available for future research, with an infrastructure that allows for recontacting participants. MethodsThe GeNepher data- and biobank is an ongoing data- and sample collection that includes patients and family members with known and/or suspected MKD. With a tiered approach participants can give broad consent for including their 1) available medical data (including genetic testing results), 2) inclusion of massively parallel sequencing data for add-on analysis, and 3) additional biobank sampling (e.g. urine for tubuloids, skin biopsy for fibroblasts). Recontacting is possible for additional data collection, novel research opportunities and return of relevant findings. DiscussionThe GeNepher data- and biobank collects prospective and retrospective data from kidney disease patients and their relatives. The broad consent allows for research that extends beyond one specific research question. Herewith, this biobank aims to 1) increase the scientific knowledge based on disease mechanisms including (novel) monogenic causes, 2) study modifiers, 3) improve care, including reproduction related research questions. Furthermore, it facilitates recontacting for opportunities in treatment development or when diagnose specific trials are started or specific treatment is approved. ConclusionThe GeNepher biobank is designed to support a wide range of research projects by providing access to a diverse population of patients with (suspected) MKD and has the potential to make a significant contribution to the field of rare kidney disease research.

Advancing Treatments for Rare Renal Diseases: New Hopes and Opportunities to Address a High Unmet Need

Introduction: The etiology of chronic kidney disease (CKD) is varied and complex. Diabetes and hypertension comprise 2/3 of cases and rare conditions, including inherited genetic diseases, comprise 1/3. We previously reported a 54% increase in clinical studies in CKD in the last 10 years. Hypothesizing a greater increase in rare renal disease studies, we undertook further analysis of metadata from Clinicaltrials.gov. Methods: CT.gov was searched for 49 conditions determined to be rare renal diseases posted between Jan-2003 and Dec-2022. Studies were divided into 2 time periods: P1 (2003–2012) and P2 (2013–2022) and analyzed by study type, phase, indication, primary endpoint, population, and funding. Results: Studies increased significantly in P2 versus P1 (123%, p < 0.001) with the greatest rise in observational studies (283%, p < 0.001). Interventional studies increased 93% (p < 0.01), with the greatest rise in early phases (205%, p < 0.001). The most frequent indications were LN, ADPKD, and IgA nephropathy; all increased 77–166% in P2 (p < 0.05 – p < 0.001). Proteinuria was the most frequent primary endpoint, which increased 63% (p = 0.054). Studies with pediatric populations increased 78% (p < 0.01). Most studies were nonindustry funded; however, industry-funded studies increased by 225% (p < 0.001). Conclusion: Clinical research in rare renal diseases has increased significantly in the last 10 years, particularly in glomerular diseases (GDs) and ADPKD. Proteinuria correlates with outcomes in GD, which explains the high percentage of studies with this primary endpoint. Rare renal diseases disproportionately affect children and the rise in studies with pediatric populations is encouraging. The rise in observational studies may signal an increased focus on understanding the natural course and pathophysiology of disease, which may lead to new potential therapeutic targets and future interventional studies. The increase in industry-funded studies suggests basic science is translating into industry-sponsored research.

Incorporating CNV analysis improves the yield of exome sequencing for rare monogenic disorders-an important consideration for resource-constrained settings.

Exome sequencing (ES) is a recommended first-tier diagnostic test for many rare monogenic diseases. It allows for the detection of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in coding exonic regions of the genome in a single test, and this dual analysis is a valuable approach, especially in limited resource settings. Single-nucleotide variants are well studied; however, the incorporation of copy number variant analysis tools into variant calling pipelines has not been implemented yet as a routine diagnostic test, and chromosomal microarray is still more widely used to detect copy number variants. Research shows that combined single and copy number variant analysis can lead to a diagnostic yield of up to 58%, increasing the yield with as much as 18% from the single-nucleotide variant only pipeline. Importantly, this is achieved with the consideration of computational costs only, without incurring any additional sequencing costs. This mini review provides an overview of copy number variant analysis from exome data and what the current recommendations are for this type of analysis. We also present an overview on rare monogenic disease research standard practices in resource-limited settings. We present evidence that integrating copy number variant detection tools into a standard exome sequencing analysis pipeline improves diagnostic yield and should be considered a significantly beneficial addition, with relatively low-cost implications. Routine implementation in underrepresented populations and limited resource settings will promote generation and sharing of CNV datasets and provide momentum to build core centers for this niche within genomic medicine.

The Orphan Drug Act at 40: Legislative Triumph and the Challenges of Success.

Policy Points The Orphan Drug Act (ODA) was the result of patient advocacy and by many measures has been strikingly successful. However, approximately 95% of the more than 7,000 known rare diseases still have no US Food and Drug Administration-approved treatment. The ODA's success led to sustained criticism of high drug prices, often for products that have orphan drug indications. Critics misconstrue the ODA's intent and propose reducing its incentives instead of pursuing policies focused on addressing broader prescription drug price challenges that exist in both the orphan and nonorphan drug market. Patients and their families will continue to defend the purpose and integrity of the ODA and to drive investments into rare disease research and clinical development.

PCR28 Facilitating and Accelerating Patient-Centered Outcomes Measures Awareness and Use in Clinical Research in Rare Diseases

PCR28 Facilitating and Accelerating Patient-Centered Outcomes Measures Awareness and Use in Clinical Research in Rare Diseases

PCR82 Hierarchical Clustering of Rare Diseases Based on Functional Impacts to Support the Identification of Potential Patient-Centered Outcomes Measures for Rare Diseases Research

PCR82 Hierarchical Clustering of Rare Diseases Based on Functional Impacts to Support the Identification of Potential Patient-Centered Outcomes Measures for Rare Diseases Research

Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report

Rare diseases (RD) have a prevalence of not more than 1/2000 persons in the European population, and are characterised by the difficulty experienced in obtaining a correct and timely diagnosis. According to Orphanet, 72.5% of RD have a genetic origin although 35% of them do not yet have an identified causative gene. A significant proportion of patients suspected to have a genetic RD receive an inconclusive exome/genome sequencing. Working towards the International Rare Diseases Research Consortium (IRDiRC)’s goal for 2027 to ensure that all people living with a RD receive a diagnosis within one year of coming to medical attention, the Solve-RD project aims to identify the molecular causes underlying undiagnosed RD. As part of this strategy, we developed a phenotypic similarity-based variant prioritization methodology comparing submitted cases with other submitted cases and with known RD in Orphanet. Three complementary approaches based on phenotypic similarity calculations using the Human Phenotype Ontology (HPO), the Orphanet Rare Diseases Ontology (ORDO) and the HPO-ORDO Ontological Module (HOOM) were developed; genomic data reanalysis was performed by the RD-Connect Genome-Phenome Analysis Platform (GPAP). The methodology was tested in 4 exemplary cases discussed with experts from European Reference Networks. Variants of interest (pathogenic or likely pathogenic) were detected in 8.8% of the 725 cases clustered by similarity calculations. Diagnostic hypotheses were validated in 42.1% of them and needed further exploration in another 10.9%. Based on the promising results, we are devising an automated standardized phenotypic-based re-analysis pipeline to be applied to the entire unsolved cases cohort.

Clinical research progress of spinal epidural lipomatosis

To review the clinical research progress of spinal epidural lipomatosis (SEL). The clinical studies on SEL at home and abroad in recent years were extensively reviewed, and the pathogenesis, clinical and imaging manifestations, and treatment status of SEL were summarized and analyzed. SEL is a disease characterized by compression of the spinal cord and nerve roots due to abnormal accumulation of epidural adipose tissue in the spinal canal. Its prevalence and diagnosis rate are low and the pathogenesis is not fully understood. MRI is the most sensitive and specific diagnostic test for SEL. Surgical decompression and removal of excess adipose tissue are the only options for patients with acute SEL or those who have failed conservative management, and conservative management should be considered for other patients. SEL is a rare disease and related research still needs to be improved. In the future, high-quality, multi-center and large-sample studies will be of great significance for evaluating the choice of treatment methods and effectiveness of SEL patients.

Next-generation sequencing-based newborn screening initiatives in Europe: an overview

Aim: This article describes results from a survey targeting healthcare professionals (HCPs) leading newborn screening (NBS) initiatives in Europe. The survey was developed within the framework of a dedicated working group set up by the International Rare Diseases Research Consortium (IRDiRC) to gather collective efforts relating to NBS. The objectives of the survey were to gain a better understanding of approaches being tested for the expansion of NBS and to raise awareness of the significant momentum across Europe to evaluate novel technologies for use in future NBS programs. Methods: A web-based survey including 57 questions was developed to gather information about genomic newborn screening initiatives in Europe that are using next-generation sequencing (NGS) as a first-tier test. Responses were analyzed qualitatively, and aggregated results are presented herein. The identity of some initiatives is not presented to preserve confidentiality. Results: The findings of the survey indicated that most initiatives are in the planning stage and have not yet started. Although all 14 studies are heterogeneous in design, there is broad consensus that NGS approaches to NBS will, in the short term, be implemented in parallel with current screening programs. The results of this survey can be used to inform the design of studies still in the early planning stages. Conclusion: Here, we provide an overview of NGS-based initiatives in Europe. Importantly, the initiatives described herein will generate evidence to evaluate the utility and feasibility of NGS approaches to NBS, thereby shortening the pathway to responsible implementation of NGS in NBS and informing future research efforts.

TRANSFORMING BRAIN CANCER TREATMENT, CARE AND RESEARCH: A CASE STUDY OF A SPECIALISED NATIONAL DIGITAL LEARNING AND NETWORKING PLATFORM FOR NHS HEALTH PROFESSIONALS

Abstract AIMS The aim of this case study is to highlight the outcomes of a specialized digital learning platform, the Tessa Jowell Academy, to share excellence and jointly tackle challenges in brain cancer treatment, research and care. The free platform is co-designed with the professional community to address unmet needs and offers members features such as virtual courses, a clinical trial finder and a peer-to-peer learning service. METHOD Performance data has been collected over the last 12 months from: online member surveys and platform data (workshop registrations, member registrations, member logins, resource downloads, video views, certificate downloads, feature requests, clinical trial updates and national network sign-ups). RESULTS The platform has over 800 member registrations from 29 NHS hospitals from a range of disciplines. There have been: 42 peers matched through the platform, 19 clinical trials added, 4 national networks set-up and 35 workshops delivered to 1200 attendees live and on-demand. Common themes from member feedback include increased learning and networking opportunities, increased specialist support, improved confidence in MDT participation and increased knowledge of other sub-specialties. CONCLUSIONS It is well evidenced that specialized knowledge sharing between centres can contribute to better outcomes, improved patient satisfaction and access to research for rare diseases. This case study highlights the national demand and potential benefits of a specialized, national digital learning platform for NHS professionals working in brain cancer. As the platform grows, the impact will continue to be measured on a national level.

Supporting the translation of multiscale research in rare disease.

Summary: In anticipation of our upcoming Special Issue, ‘Translating Multiscale Research in Rare Disease’, we celebrate the strides taken in rare disease research that are improving patient diagnosis, prognosis and treatment.

A comprehensive approach toward research and management of rare diseases

A comprehensive approach toward research and management of rare diseases

Diagnosis, treatment, and research status of rare diseases related to birth defects.

Rare diseases are diseases that occur at low prevalence, and most of them are chronic and serious diseases that are often life-threatening. Currently, there is no unified definition for rare diseases. The diagnosis, treatment, and research of rare diseases have become the focus of medicine and biopharmacology, as well as the breakthrough point of clinical and basic research. Birth defects are the hard-hit area of rare diseases and the frontiers of its research. Since most of these defects have a genetic basis, early screening and diagnosis have important scientific value and social significance for the prevention and control of such diseases. At present, there is no effective treatment for most rare diseases, but progress in prenatal diagnosis and screening can prevent the occurrence of diseases and help prevent and treat rare diseases. This article discusses the progress in genetic-related birth defects and rare diseases.

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases.

The positive impact on translational research of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), a non-profit foundation focused on amyotrophic lateral sclerosis. Convergence of ex-ante evaluation and ex-post outcomes when goals are set upfront.

Charities investing on rare disease research greatly contribute to generate ground-breaking knowledge with the clear goal of finding a cure for their condition of interest. Although the amount of their investments may be relatively small compared to major funders, the advocacy groups' clear mission promotes innovative research and aggregates highly motivated and mission-oriented scientists. Here, we illustrate the case of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), the main Italian funding agency entirely dedicated to amyotrophic lateral sclerosis research. An international benchmark analysis of publications derived from AriSLA-funded projects indicated that their mean relative citation ratio values (iCite dashboard, National Institutes of Health, U.S.) were very high, suggesting a strong influence on the referring international scientific community. An interesting trend of research toward translation based on the "triangle of biomedicine" and paper citations (iCite) was also observed. Qualitative analysis on researchers' accomplishments was convergent with the bibliometric data, indicating a high level of performance of several working groups, lines of research that speak of progression toward clinical translation, and one study that has progressed from the investigation of cellular mechanisms to a Phase 2 international clinical trial. The key elements of the success of the AriSLA investment lie in: (i) the clear definition of the objectives (research with potential impact on patients, no matter how far), (ii) a rigorous peer-review process entrusted to an international panel of experts, (iii) diversification of the portfolio with ad hoc selection criteria, which also contributed to bringing new experts and younger scientists to the field, and (iv) a close interaction of AriSLA stakeholders with scientists, who developed a strong sense of belonging. Periodic review of the portfolio of investments is a vital practice for funding agencies. Sharing information between funding agencies about their own policies and research assessment methods and outcomes help guide the international debate on funding strategies and research directions to be undertaken, particularly in the field of rare diseases, where synergy is a relevant enabling factor.

Advancing Understanding of Inequities in Rare Disease Genomics

Advances in genomic research have facilitated rare disease diagnosis for thousands of individuals. Unfortunately, the benefits of advanced genetic diagnostic technology are not distributed equitably among the population, as has been seen in many other health care contexts. Quantifying and describing inequities in genetic diagnostic yield is inherently challenging due to barriers to both clinical and research genetic testing. We therefore present an implementation protocol developed to expand access to our rare disease genomic research study and to further understand existing inequities. The Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers research genome sequencing to individuals with rare disease who remain genetically undiagnosed through direct interaction with the individual or family. This presents an opportunity for diagnosis beyond the clinical context, thus eliminating many barriers to access. An initial goal of RGP was to equalize access to genomic sequencing by decoupling testing access from proximity to a major medical center and physician referral. However, study participants over the initial 3 years of this project were predominantly white and well resourced. To further understand and address the lack of diversity within RGP, we developed a novel protocol embedded within the larger RGP study, in an approach informed by an implementation science framework. The aims of this protocol were: (1) to diversify recruitment and enrollment within RGP; (2) understand the process and context of implementing genomic medicine for rare disease diagnosis; and (3) investigate the value of a diagnosis for underserved populations. Improved understanding of existing inequities and potential strategies to address them are needed to advance equity in rare disease genetic diagnosis and research. In addition to the moral imperative of equity in genomic medicine, this approach is critical in order to fully understand the genomic underpinnings of rare disease.

Why are Patient Registries Key to Accelerating Rare Disease Research?

The World Health Organization (WHO) defines Rare disease as a disorder which affects less than 6.5 to 10 per 10,000 people (Rabiei). In the European Union, the definition narrows down to 5 in 10,000 people, while in the United States, a rare disease is defined as a condition that affects fewer than 200,000 people. By these definitions there are more than 6800 (“Rare Diseases”) rare diseases. While the exact cause for most rare diseases are not known, several of these are usually traced to mutations in a single gene, which would essentially be passed down from one generation to the next. That is the reason we see these rare diseases running in families.

REDCap and the National Mesothelioma Virtual Bank-a scalable and sustainable model for rare disease biorepositories.

Rare disease research requires data sharing networks to power translational studies. We describe novel use of Research Electronic Data Capture (REDCap), a web application for managing clinical data, by the National Mesothelioma Virtual Bank, a federated biospecimen, and data sharing network. National Mesothelioma Virtual Bank (NMVB) uses REDCap to integrate honest broker activities, enabling biospecimen and associated clinical data provisioning to investigators. A Web Portal Query tool was developed to source and visualize REDCap data in interactive, faceted search, enabling cohort discovery by public users. An AWS Lambda function behind an API calculates the counts visually presented, while protecting record level data. The user-friendly interface, quick responsiveness, automatic generation from REDCap, and flexibility to new data, was engineered to sustain the NMVB research community. NMVB implementations enabled a network of 8 research institutions with over 2000 mesothelioma cases, including clinical annotations and biospecimens, and public users' cohort discovery and summary statistics. NMVB usage and impact is demonstrated by high website visits (>150 unique queries per month), resource use requests (>50 letter of interests), and citations (>900) to papers published using NMVB resources. NMVB's REDCap implementation and query tool is a framework for implementing federated and integrated rare disease biobanks and registries. Advantages of this framework include being low-cost, modular, scalable, and efficient. Future advances to NVMB's implementations will include incorporation of -omics data and development of downstream analysis tools to advance mesothelioma and rare disease research. NVMB presents a framework for integrating biobanks and patient registries to enable translational research for rare diseases.

Unveiling the hidden: revisiting the potential of old genetic data for rare disease research.

Unveiling the hidden: revisiting the potential of old genetic data for rare disease research.