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\"Pulitzer Prize-winning reporter Amy Dockser Marcus shows what happened when a group of parents joined forces with doctors and researchers to try to save children's lives. Parents whose children had been diagnosed with the rare and fatal genetic condition Niemann-Pick Type C disease recognized there would never be a treatment in time to save their children if things stayed the same, so the parents set up a collaboration with researchers and doctors in search of a cure. Their social experiment reveals new pathways for treating disease and conducting research\"-- Provided by publisher.

The prioritization of clinical practice guideline (CPG) efforts is particularly challenging for rare genetic neurodevelopmental disorders given the large number of (ultra)rare conditions and limited resources. We aimed to establish criteria for the priority-setting of CPG topics within the European Reference Network (ERN) Intellectual disability, TeleHealth, Autism, and Congenital Anomalies (ITHACA) based on stakeholder input. Sets of priority-setting criteria for etiology-specific CPGs and shared health topic CPGs (across etiologies) were generated using a 2-phase consensus process. The first phase consisted of initial criteria generation, internal feedback from the ERN ITHACA Executive Committee and Patient Advisory Board, and stakeholder input through an open survey. The second phase consisted of a 2-round modified Delphi and consensus meeting with an expert panel consisting of patient advocates, clinicians, and methodologists. The final sets of priority-setting criteria included absence of existing guidance, high burden for affected individuals and families, and specific health risks requiring adaptation from usual care. In addition, complexity and treatment availability were included for etiology-specific CPGs and common occurrence and societal burden were included for CPGs for shared health topics. Availability and interest of clinical experts and patient organizations were considered required to produce CPGs; shared health topics addressed through dedicated CPGs need to be universal across etiologies. Aligning with stakeholder perspectives in priority-setting is required to allocate scarce resources to the development of high-priority CPGs for rare conditions. Priority-setting criteria specific to the rare condition context were identified. CPG development was considered a particular priority important for complex conditions and/or health care and where care is nonstandard. Practice variation was not selected as a priority-setting criterion. [Display omitted] •We established priority-setting criteria for European rare condition guidelines.•Complexity and need to deviate from usual care indicated guideline priority.•Practice variation and feasibility of implementation were not selected.•Priority-setting is shaped by the context and goals of guideline development.

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG , PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants. A flexible and compact database containing rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project enables the identification of new disease-causing genes.

Genomic matchmaking-the process of identifying individuals with overlapping phenotypes and rare variants in the same gene-is an important tool facilitating gene discoveries for unsolved rare genetic disease (RGD) patients. Current approaches are two-sided, meaning both patients being matched must have the same candidate gene flagged. This limits the number of RGD patients eligible for matchmaking. One-sided matchmaking, in which a gene of interest is queried in the genome-wide sequencing data of RGD patients, would make matchmaking possible for previously undiscoverable individuals. However, platforms and workflows for this approach have not been well established. We released a beta version of the One-Sided Matching Portal (OSMP), a platform capable of performing one-sided matchmaking queries across thousands of participants stored in genomic databases. The OSMP returns variant-level and participant-level information on each variant occurrence (VO) identified in a queried gene. A workflow for one-sided matchmaking was developed so that researchers could prioritize the many VOs returned from a given query. This workflow was tested through pilot studies where two sets of genes were queried in over 2500 individuals: 130 genes that were newly associated with disease in OMIM and 178 novel candidate genes that were not associated with a disease-gene association in OMIM. These pilots returned a large number of initial VOs (12,872 and 20,308, respectively); however, the workflow filtered out over 99.8% of these VOs prior to review by a participant's clinician. Filters on participant-level information, including variant zygosity, participant phenotype, and whether a variant was also present in unaffected participants, were effective at reducing the number of false positive matches. As demonstrated through the two pilot studies, one-sided matchmaking queries can be efficiently performed using the OSMP. The availability of variant-level and participant-level data is key to ensuring this approach is practical for researchers.

In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients’ lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.

Rare diseases refer to a group of neglected diseases with low prevalence that face challenges in diagnostics as well as therapeutics due to phenotypic heterogeneity and ineffective clinical trials. In this study, we evaluated two novel analogs of hydroxyethylamine & phthalimide (LTC-181 and LTC-1717) for their potential effect on the epimerase activity of mutant GNE proteins associated with GNE myopathy. GNE gene encodes a key bifunctional sialic acid biosynthetic enzyme, UDP-N-acetyl Glucosamine 2-epimerase/N-acetyl Mannosamine Kinase; GNE). The compounds have significantly increased the epimerase activity of r-F307C-GNE and r-A555V-GNE mutant proteins in vitro. Reduced GNE epimerase activity and sialic acid content in muscle cell-based model for GNE function (SKM-GNEHz) was increased by 2-fold after addition of these compounds. The proteomic study showed that the compounds affected cytoskeletal organization, autophagy and muscle atrophy. Also, treatment with analogs enhanced the cell viability of SKM-GNEHz cells with increased F-actin polymerization and cell migration, thereby, restoring GNE deficient function. Additionally, effect of these compounds was observed with enhanced autophagy and reduced muscle atrophy function in GNE deficient muscle cell. Docking and interaction studies showed that LTC-1717 stabilize GNE better than LTC-181, indicating better therapeutic potential. Overall, this study indicates that HEA-phthalimide analog could be promising leads for treating GNE myopathy.

Rare genetic diseases are rare by themselves with prevalence of 1 in 25,000, but collectively they are a significant cause of morbidity and mortality. Till date, collectively there are more than 9,000 rare diseases documented, which impose a devastating impact on patients, their families, and the healthcare system, including enormous societal burden. Obtaining a conclusive diagnosis for a patient with a rare genetic disease can be long and gruelling. For some patients it takes months or years to receive a definite diagnosis, and around 50% of the patients remain undiagnosed even with expert clinical and advanced high-end laboratory investigations. Owing to the large population and practice of consanguinity the Indian population is a pool of indigenous variants and unreported phenotypes or diseases. A mission program on pediatric rare diseases is an unparalleled initiative to study unique clinical conditions via the use of latest state-of-art technologies and with the combination of a mulit-omics approach. Our initiative will not only provide diagnosis to patients with rare disease but also build a platform for translational research for rare disease screening, management, and treatment.

In the time of advancing medical technology, there is a critical issue concerning the misdiagnosis of diseases. The aim of this research is to significantly reduce the occurrence of misdiagnoses in medical practice by leveraging hypergraphs and genomic data to improve diagnostic accuracy. We have designed and implemented a sophisticated computational framework for phenotype-driven disease prediction that leverages hypergraphs and genomic data to enhance the accuracy of disease identification, leading to more precise and timely treatments for patients. The study employed robust ranking algorithms, on a sample of 2130 diseases, 4655 genes and 9541 phenotypes collected from reliable sources of Orphanet and Human Phenotype Ontology (HPO) database to achieve highly favorable outcomes. The proposed method outperforms existing state-of-the-art tools such as Phenomizer and GCN, in terms of both prediction accuracy and processing speed. Notably, it captures 50% of causal genes within the top 10 predictions and 85% within the top 100 predictions and the algorithm maintains a high accuracy rate of 98.09% for the top-ranked gene. In conclusion, our study demonstrated the effectiveness of robust ranking algorithms and hypergraph framework in achieving accurate and reliable results for disease diagnosis. While the study provides valuable insights, it is important to note its limitations, such as the sample size and scope of diseases considered. Future research could explore the integration of additional data sources and refinement of algorithms to further enhance diagnostic capabilities. Overall, this study underscores the potential of algorithmic hypergraph based approaches in advancing medical diagnostics and improving healthcare delivery.

Rare genetic diseases are a group of life-threatening disorders affecting significant populations worldwide and posing substantial challenges to healthcare systems globally. India, with its vast population, is also no exception. The country harbors millions of individuals affected by these fatal disorders, which often result from mutations in a single gene. The emergence of CRISPR-Cas9 technology, however, has ushered in a new era of hope in genetic therapies. CRISPR-based treatments hold the potential to precisely edit and correct disease-causing mutations, offering tailored solutions for rare genetic diseases in India. This review explores the landscape of rare genetic diseases in India along with national policies and major challenges, and examines the implications of CRISPR-based therapies for potential cure. It delves into the potential of this technology in providing personalized and effective treatments. However, alongside these promising prospects, some ethical considerations, regulatory challenges, and concerns about the accessibility of CRISPR therapies are also discussed since addressing these issues is crucial for harnessing the full power of CRISPR in tackling rare genetic diseases in India. By taking a multidisciplinary approach that combines scientific advancements, ethical principles, and regulatory frameworks, these complexities can be reconciled, paving the way for innovative and impactful healthcare solutions for rare diseases in India.