An algorithm to identify patients aged 0-3 with rare genetic disorders.

BACKGROUND: With over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured electronic medical record data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. We sought to develop a digital phenotyping algorithm (PheIndex) using electronic medical records to identify children aged 0-3 diagnosed with genetic disorders or who present with illness with an increased risk for genetic disorders. RESULTS: Through expert opinion, we established 13 criteria for the algorithm and derived a score and a classification. The performance of each criterion and the classification were validated by chart review. PheIndex identified 1,088 children out of 93,154 live births who may be at an increased risk for genetic disorders. Chart review demonstrated that the algorithm achieved 90% sensitivity, 97% specificity, and 94% accuracy. CONCLUSIONS: The PheIndex algorithm can help identify when a rare genetic disorder may be present, alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist.

Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project.

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. METHODS: We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. RESULTS: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. CONCLUSIONS: Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

A quantitative and qualitative analysis of patient group narratives suggests common biopsychosocial red flags of undiagnosed rare disease.

BACKGROUND: The 'diagnostic odyssey' is a common challenge faced by patients living with rare diseases and poses a significant burden for patients, their families and carers, and the healthcare system. The diagnosis of rare diseases in clinical settings is challenging, with patients typically experiencing a multitude of unnecessary tests and procedures. To improve diagnosis of rare disease, clinicians require evidence-based guidance on when their patient may be presenting with a rare disease. This study aims to identify common experiences amongst patients with rare diseases, to inform a series of 'red flags' that can aid diagnosis of rare diseases in non-specialist settings. A questionnaire was developed by Medics for Rare Diseases, informed by the experiences of clinicians, rare disease patients and patient advocates, and was shared with UK-based rare disease patient groups. Study participants were engaged via social media platforms, blogs and email newsletters of three umbrella rare disease organisations. The questionnaire, comprising 22 questions, was designed to identify typical experiences relating to physical and psychosocial manifestations and presentation of disease, patient interactions with healthcare providers, and family history. RESULTS: Questionnaire responses were received from 79 different rare disease patient groups and the common experiences identified were used to inform seven red flags of rare disease: multi-system involvement (3 or more); genetic inheritance pattern; continued presentation throughout childhood and adulthood; difficulties at school, especially relating to absences, difficulty participating in physical education and experiences of bullying or social isolation; multiple specialist referrals; extended period with unexplained symptoms; and misdiagnosis. In light of the red flags identified, recommendations for primary care and education settings have been proposed, focusing on the need for holistic assessment and awareness of both physical and psychosocial factors. CONCLUSIONS: This study identified key commonalities experienced by patients with rare disease across physical and psychosocial domains, in addition to understanding patients' history and experiences with healthcare providers. These findings could be used to develop a clinical decision­making tool to support non-specialist practitioners to consider when their patient may have an undiagnosed rare condition, which may minimise the challenges of the 'diagnostic odyssey' and improve the patient experience.

The value of knowing: preferences for genetic testing to diagnose rare muscle diseases.

BACKGROUND: Genetic testing can offer early diagnosis and subsequent treatment of rare neuromuscular diseases. Options for these tests could be improved by understanding the preferences of patients for the features of different genetic tests, especially features that increase information available to patients. METHODS: We developed an online discrete-choice experiment using key attributes of currently available tests for Pompe disease with six test attributes: number of rare muscle diseases tested for with corresponding probability of diagnosis, treatment availability, time from testing to results, inclusion of secondary findings, necessity of a muscle biopsy, and average time until final diagnosis if the first test is negative. Respondents were presented a choice between two tests with different costs, with respondents randomly assigned to one of two costs. Data were analyzed using random-parameters logit. RESULTS: A total of 600 online respondents, aged 18 to 50 years, were recruited from the U.S. general population and included in the final analysis. Tests that targeted more diseases, required less time from testing to results, included information about unrelated health risks, and were linked to shorter time to the final diagnosis were preferred and associated with diseases with available treatment. Men placed relatively more importance than women on tests for diseases with available treatments. Most of the respondents would be more willing to get a genetic test that might return unrelated health information, with women exhibiting a statistically significant preference. While respondents were sensitive to cost, 30% of the sample assigned to the highest cost was willing to pay $500 for a test that could offer a diagnosis almost 2 years earlier. CONCLUSION: The results highlight the value people place on the information genetic tests can provide about their health, including faster diagnosis of rare, unexplained muscle weakness, but also the value of tests for multiple diseases, diseases without treatments, and incidental findings. An earlier time to diagnosis can provide faster access to treatment and an end to the diagnostic journey, which patients highly prefer.

Landscape analysis of available European data sources amenable for machine learning and recommendations on usability for rare diseases screening.

BACKGROUND: Patient registries and databases are essential tools for advancing clinical research in the area of rare diseases, as well as for enhancing patient care and healthcare planning. The primary aim of this study is a landscape analysis of available European data sources amenable to machine learning (ML) and their usability for Rare Diseases screening, in terms of findable, accessible, interoperable, reusable(FAIR), legal, and business considerations. Second, recommendations will be proposed to provide a better understanding of the health data ecosystem. METHODS: In the period of March 2022 to December 2022, a cross-sectional study using a semi-structured questionnaire was conducted among potential respondents, identified as main contact person of a health-related databases. The design of the self-completed questionnaire survey instrument was based on information drawn from relevant scientific publications, quantitative and qualitative research, and scoping review on challenges in mapping European rare disease (RD) databases. To determine database characteristics associated with the adherence to the FAIR principles, legal and business aspects of database management Bayesian models were fitted. RESULTS: In total, 330 unique replies were processed and analyzed, reflecting the same number of distinct databases (no duplicates included). In terms of geographical scope, we observed 24.2% (n = 80) national, 10.0% (n = 33) regional, 8.8% (n = 29) European, and 5.5% (n = 18) international registries coordinated in Europe. Over 80.0% (n = 269) of the databases were still active, with approximately 60.0% (n = 191) established after the year 2000 and 71.0% last collected new data in 2022. Regarding their geographical scope, European registries were associated with the highest overall FAIR adherence, while registries with regional and "other" geographical scope were ranked at the bottom of the list with the lowest proportion. Responders' willingness to share data as a contribution to the goals of the Screen4Care project was evaluated at the end of the survey. This question was completed by 108 respondents; however, only 18 of them (16.7%) expressed a direct willingness to contribute to the project by sharing their databases. Among them, an equal split between pro-bono and paid services was observed. CONCLUSIONS: The most important results of our study demonstrate not enough sufficient FAIR principles adherence and low willingness of the EU health databases to share patient information, combined with some legislation incapacities, resulting in barriers to the secondary use of data.

Patient preferences in genetic newborn screening for rare diseases: study protocol.

INTRODUCTION: Rare diseases (RDs) collectively impact over 30 million people in Europe. Most individual conditions have a low prevalence which has resulted in a lack of research and expertise in this field, especially regarding genetic newborn screening (gNBS). There is increasing recognition of the importance of incorporating patients' needs and general public perspectives into the shared decision-making process regarding gNBS. This study is part of the Innovative Medicine Initiative project Screen4Care which aims at shortening the diagnostic journey for RDs by accelerating diagnosis for patients living with RDs through gNBS and the use of digital technologies, such as artificial intelligence and machine learning. Our objective will be to assess expecting parent's perspectives, attitudes and preferences regarding gNBS for RDs in Italy and Germany. METHODS AND ANALYSIS: A mixed method approach will assess perspectives, attitudes and preferences of (1) expecting parents seeking genetic consultation and (2) 'healthy' expecting parents from the general population in two countries (Germany and Italy). Focus groups and interviews using the nominal group technique and ranking exercises will be performed (qualitative phase). The results will inform the treatment of attributes to be assessed via a survey and a discrete choice experiment (DCE). The total recruitment sample will be 2084 participants (approximatively 1000 participants in each country for the online survey). A combination of thematic qualitative and logit-based quantitative approaches will be used to analyse the results of the study. ETHICS AND DISSEMINATION: This study has been approved by the Erlangen University Ethics Committee (22-246_1-B), the Freiburg University Ethics Committee (23-1005 S1-AV) and clinical centres in Italy (University of FerraraCE: 357/2023/Oss/AOUFe and Hospedale Bambino Gesu: No.2997 of 2 November 2023, Prot. No. _902) and approved for data storage and handling at the Uppsala University (2022-05806-01). The dissemination of the results will be ensured via scientific journal publication (open access).

Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Genomic Answers for Kids: Toward more equitable access to genomic testing for rare diseases in rural populations.

Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment. Primary care providers (PCPs) at local clinics, though sometimes suspicious of a potential benefit of genetic testing for their patients, have significant constraints in pursuing it themselves and rely on referrals to specialists. Yet, these referrals are typically followed by long waitlists and significant delays in clinical assessment, insurance clearance, testing, and initiation of diagnosis-informed care management. Not only is this process time intensive, but it also often requires multiple visits to urban medical centers for which distance may be a significant barrier to rural families. Therefore, providing early, "direct-to-provider" (DTP) local access to unrestrictive genomic testing is likely to help speed up diagnostic times and access to care for RD patients in rural communities. In a pilot study with a PCP clinic in rural Kansas, we observed a minimum 5.5 months shortening of time to diagnosis through the DTP exome sequencing program as compared to rural patients receiving genetic testing through the "traditional" PCP-referral-to-specialist scheme. We share our experience to encourage future partnerships beyond our center. Our efforts represent just one step in fostering greater diversity and equity in genomic studies.

Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.

Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin-proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey.

A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

Explicable prioritization of genetic variants by integration of rule-based and machine learning algorithms for diagnosis of rare Mendelian disorders.

BACKGROUND: In the process of finding the causative variant of rare diseases, accurate assessment and prioritization of genetic variants is essential. Previous variant prioritization tools mainly depend on the in-silico prediction of the pathogenicity of variants, which results in low sensitivity and difficulty in interpreting the prioritization result. In this study, we propose an explainable algorithm for variant prioritization, named 3ASC, with higher sensitivity and ability to annotate evidence used for prioritization. 3ASC annotates each variant with the 28 criteria defined by the ACMG/AMP genome interpretation guidelines and features related to the clinical interpretation of the variants. The system can explain the result based on annotated evidence and feature contributions. RESULTS: We trained various machine learning algorithms using in-house patient data. The performance of variant ranking was assessed using the recall rate of identifying causative variants in the top-ranked variants. The best practice model was a random forest classifier that showed top 1 recall of 85.6% and top 3 recall of 94.4%. The 3ASC annotates the ACMG/AMP criteria for each genetic variant of a patient so that clinical geneticists can interpret the result as in the CAGI6 SickKids challenge. In the challenge, 3ASC identified causal genes for 10 out of 14 patient cases, with evidence of decreased gene expression for 6 cases. Among them, two genes (HDAC8 and CASK) had decreased gene expression profiles confirmed by transcriptome data. CONCLUSIONS: 3ASC can prioritize genetic variants with higher sensitivity compared to previous methods by integrating various features related to clinical interpretation, including features related to false positive risk such as quality control and disease inheritance pattern. The system allows interpretation of each variant based on the ACMG/AMP criteria and feature contribution assessed using explainable AI techniques.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Losing Our Way In A Rare Disease Diagnostic Odyssey.

A mother shares the story of her son's rare disease diagnostic journey and how providers failed them both along the way.

Difficulties in disclosing secondary findings by facilities performing comprehensive germline genetic testing for rare diseases in Japan.

In Japan, a limited number of laboratories perform comprehensive genetic testing for rare diseases; this study investigated the attitudes of these laboratories toward the disclosure of secondary finding (SF). Following a preliminary survey, we identified laboratories conducting comprehensive genetic testing for participation. Subsequently, an online survey involving 20 selected facilities was conducted. The response rate was 80% (16/20). Of the 14 facilities, 71.4% had SFs. While 42.9% of them had a policy to disclose SFs with clinical utility, only 14.3% actively searched for actionable variants that could be included in the American College of Medical Genetics and Genomics list. Japan was less enthusiastic than the USA regarding SF disclosure. With regard to the reasons for not disclosing SFs, the factors "the thought that participants may have a low desire for SFs" and "uncertainty regarding their wish" were considered more important than in the USA. A content analysis of what was sought as a solution to this difficulty revealed a need to improve databases on pathogenicity and actionability and collect public thoughts on the issue. The factor "to promote entry in research" was not considered a critical reason for disclosing SFs, indicating that the thirst for information was not possibly due to anxiety but rather due to scientific interest. Japanese medical professionals may not be confident that society requires the disclosure of SFs. To improve the environment, it is necessary to survey the public regarding their thoughts on SF disclosure and discuss this issue in society.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Diagnosis of alpha-Mannosidosis: Practical approaches to reducing diagnostic delays in this ultra-rare disease.

Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent alpha-mannosidase in lysosomes, which leads to intracellular accumulation of mannose-containing oligosaccharides. Diagnosis of alpha-mannosidosis is often delayed, in part because of the rarity of the disease, its gradual onset and heterogeneity of presentation, but also because of the similarity of many signs and symptoms of the disease to those of other lysosomal diseases. Treatment of alpha-mannosidosis was previously limited to hematopoietic stem cell transplantation, but outcomes are variable and not all patients are eligible or have a suitable donor. Recently, an enzyme replacement therapy, recombinant human alpha-mannosidase (velmanase alfa), was approved for the treatment of non-neurological manifestations in adult and pediatric patients with alpha-mannosidosis. Treatment with velmanase alfa reduces serum levels of oligosaccharides, increases levels of immunoglobulin G, and improves patients' functional capacity and quality of life, although it is not effective for the neurologic phenotype because it does not cross the blood-brain barrier. Since the effects of velmanase alfa are more marked in children than adults, early diagnosis to allow early initiation of treatment has become more important. To support this, patient, parent/caregiver, and clinician awareness and education is imperative. A number of approaches can be taken to meet this goal, such as the development of disease registries, validated diagnostic algorithms, and screening tools, improved under-/post-graduate clinician education, easily accessible and reliable information for patients/families (such as that made available on the internet), and the formation of patient advocacy groups. Such approaches may raise awareness of alpha-mannosidosis, reduce the diagnostic delay and thus improve the lives of those affected.

Rare bleeding disorders: Real-world data from a Spanish tertiary hospital.

INTRODUCTION: Due to their low prevalence, rare bleeding disorders (RBDs) remain poorly characterized. AIM: To gain insight of RBDs through our clinical practice. METHODS: Retrospective study of the medical records of RBD patients followed up at the Central University Hospital of Asturias between January 2019 and December 2022. RESULTS: A total of 149 patients were included. Factor (F) VII (44 %) and FXI (40 %) deficiencies were the most common diagnosed coagulopathies. Most of the patients were asymptomatic (60.4 %) and the most frequent type of bleeding were mucocutaneous and after surgery. All replacement treatments were administered on demand and no patient was on a prophylaxis regimen. Currently available products were safe; allergic reactions after administration of plasma were the most frequent complication. Genetic analysis, carried out on 55 patients (37 %), showed that the most frequent mutations in RBDs are of missense type (71.9 %). We identified 11 different novel genetic alterations in affected genes. The c.802C > T (p.Arg268Cys) variant, previously described, was identified in 71 % (15 of 21) of the patients with FXI deficiency genotyped and none were related (probable founder effect). CONCLUSION: Our study on an unusual large single center cohort of RBD patients portrays location-dependent distinct genetic drives and clinical practice particularities.

Rare Disease Day: Amplifying voices, advocating hope.

Every year on February 28, the global community comes together to observe Rare Disease Day, a day dedicated to raising awareness and understanding for the millions of individuals who live with rare disorders. While individual rare diseases may seem uncommon, their collective impact is significant, affecting the lives of countless families and communities worldwide. This day serves as a crucial platform to amplify the voices of those affected, advocate for increased research and support, and inspire hope for a future where rare diseases can be prevented, diagnosed earlier, and effectively treated.