Int J Comput Assist Radiol Surg. 2025 Feb;20(2):415-431. doi: 10.1007/s11548-024-03309-6. Epub 2024 Dec 29.

ABSTRACT

PURPOSE: This study explores the use of deep generative models to create synthetic ultrasound images for the detection of hemarthrosis in hemophilia patients. Addressing the challenge of sparse datasets in rare disease diagnostics, the study aims to enhance AI model robustness and accuracy through the integration of domain knowledge into the synthetic image generation process.

METHODS: The study employed two ultrasound datasets: a base dataset (Db) of knee recess distension images from non-hemophiliac patients and a target dataset (Dt) of hemarthrosis images from hemophiliac patients. The synthetic generation framework included a content generator (Gc) trained on Db and a context generator (Gs) to adapt these images to match Dt's context. This approach generated a synthetic target dataset (Ds), primed for AI training in rare disease research. The assessment of synthetic image generation involved expert evaluations, statistical analysis, and the use of domain-invariant perceptual distance and Fréchet inception distance for quality measurement.

RESULTS: Expert evaluation revealed that images produced by our synthetic generation framework were comparable to real ones, with no significant difference in overall quality or anatomical accuracy. Additionally, the use of synthetic data in training convolutional neural networks demonstrated robustness in detecting hemarthrosis, especially with limited sample sizes.

CONCLUSION: This study presents a novel approach for generating synthetic ultrasound images for rare disease detection, such as hemarthrosis in hemophiliac knees. By leveraging deep generative models and integrating domain knowledge, the proposed framework successfully addresses the limitations of sparse datasets and enhances AI model training and robustness. The synthetic images produced are of high quality and contribute significantly to AI-driven diagnostics in rare diseases, highlighting the potential of synthetic data in medical imaging.

PMID:39739290 | DOI:10.1007/s11548-024-03309-6

Open Vet J. 2024 Nov;14(11):3063-3073. doi: 10.5455/OVJ.2024.v14.i11.35. Epub 2024 Nov 30.

ABSTRACT

BACKGROUND: Corneal squamous cell carcinoma (cSCC) is a rare neoplasm of dogs that can be treated with various modalities, principally by superficial keratectomy (SK) surgery. It is common to treat cSCC with multiple adjunctive therapies, but this may not always be practical for clinicians, clients, or patients.

AIM: This retrospective study describes the signalment of affected dogs, concurrent medical therapy, and success rate of surgical treatment of cSCC with SK surgery alone or in combination with adjunct therapy.

METHODS: Eligible dogs undergoing SK surgery for histologically confirmed cSCC were selected from medical records (2009-2024) of Animal Eye Care, Melbourne. Records were examined for cSCC recurrence at follow up.

RESULTS: Between January 2009 and August 2024, 16 eyes from 14 dogs (5 male; 35.7% (37.5% eyes), 9 female; 64.3% (62.5% eyes) had a confirmed histopathological diagnosis of cSCC following SK surgery. All cases were diagnosed within the last 9 years. There was a notable predilection of brachycephalic breeds (85.7% of dogs; 81.3% of eyes) with pugs the most overrepresented (42.9% of dogs; 37.5% of eyes). The average age at diagnosis was 8.7 years (range 2.1-13.8). Tumor recurrence occurred in two cases following incomplete excision, with no tumor recurrence reported following a second SK surgery. Adjunctive therapy was used in four cases and included cryotherapy and topical interferon alpha-2a. At the time of diagnosis, 12 out of 16 eyes had been treated previously with topical immunomodulatory therapy. Prevalence data varied but peaked in 2021 with 0.14% of total patients and 0.82% of all brachycephalic patients diagnosed with cSCC.

CONCLUSION: Complete excision of cSCC by SK surgery is effective for preventing the recurrence of cSCC in dogs, even in the absence of adjunctive therapies. Dogs with chronic corneal inflammatory conditions, particularly brachycephalic breeds, are at higher risk for developing cSCC. Corneal SCC should be suspected in middle-aged brachycephalic dogs presenting with proliferative, raised, or hyperaemic corneal lesions.

PMID:39737039 | PMC:PMC11682761 | DOI:10.5455/OVJ.2024.v14.i11.35

J Med Genet. 2024 Dec 31:jmg-2024-109951. doi: 10.1136/jmg-2024-109951. Online ahead of print.

ABSTRACT

BACKGROUND: Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in ARID1B patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.

METHODS: This study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, ARID1B patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).

RESULTS: In the clonazepam group (n=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed 'no change' after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (n=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.

CONCLUSIONS: Our approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in ARID1B patients.

TRIAL REGISTRATION NUMBER: EUCTR2019-003558-98, ISRCTN11225608.

PMID:39740803 | DOI:10.1136/jmg-2024-109951

Echocardiography. 2025 Jan;42(1):e70070. doi: 10.1111/echo.70070.

ABSTRACT

We present a case of a 72-year-old female patient with dyspnea and lipothymia. Echocardiography demonstrates an intracavitary cystic mass that fills almost all left atria causing supravalvular obstruction. The magnetic resonance image revealed a 53 × 47 × 48 mm heterogeneous mass with regular edges, tissue characterization suggested myxoma. The patient underwent surgical resection, histopathologic study was compatible with sarcoma. This case underscores the importance of multimodal imaging for an accurate approach and early diagnosis of cardiac intracavitary masses.

PMID:39737702 | DOI:10.1111/echo.70070

Appl Health Econ Health Policy. 2025 Mar;23(2):209-229. doi: 10.1007/s40258-024-00939-4. Epub 2024 Dec 28.

ABSTRACT

OBJECTIVE: This article reviews the assessment pathways that have been implemented worldwide to facilitate access to drugs for patients with rare diseases.

METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used to conduct a systematic literature review. The Ovid (Embase/MEDLINE), Cochrane, Web of Science, Econlit, National Institute of Health Research, Centre for Reviews and Dissemination, and International Network of Agencies for Health Technology Assessment databases were searched. Two independent reviewers screened all titles and abstracts; one reviewer did the full-text review and data extraction. Data were extracted on study general characteristics, general aspects of rare diseases, source of funding, allocation of public resources (e.g., use of health technology assessment), and pricing strategies. Assessment pathways were classified as: (1) separate processes; (2) exception to standard process; (3) standard process with no change; and (4) alternative process. Each assessment pathway was characterized based on its unique characteristics specific to rare diseases focusing on whether they targeted specific aspects of the process, utilized particular methodologies during the evaluation of the evidence, or considered specific attributes in the recommendation.

RESULTS: A total of 5604 unique citations were screened and 158 were included for data extraction. Sixty-one assessment pathways were identified in 43 countries, categorized as separate processes (37%), exceptions to standard processes (32%), standard processes with no changes (26%), and alternative processes (5%). Some countries (10/43; 23%) have more than one assessment pathway available. Assessment pathways varied in their inclusion of a health technology assessment, source of funding, consideration of uncertainty, and pricing strategies.

CONCLUSIONS: The diversity of assessment pathways reflects the complexity of addressing access to treatments for rare diseases. Furthermore, most assessment pathways are from high-income countries; therefore, there is less clarity on what is happening in low- and middle-income countries.

PMID:39731657 | DOI:10.1007/s40258-024-00939-4

Lung Cancer. 2025 Jan;199:108035. doi: 10.1016/j.lungcan.2024.108035. Epub 2024 Dec 27.

ABSTRACT

A major paradigm shift in the diagnosis, management, and survival outcomes of early and advanced non-small cell lung cancer has transpired over the past few decades in thoracic oncology with the incorporation of molecular testing, targeted therapy, immunotherapy, neoadjuvant, and adjuvant approaches. However, transformation in the management and survival outcomes of rare lung tumors is lacking. Given the scarcity of these tumor types, randomized trials are rarely performed, and treatment is extrapolated from case series, tumor-agnostic trials, or cancers with similar histology. Literature informing the management of rare pulmonary tumors is typically limited to a single histology, unique features, or extraordinary responses to therapy. Few resources detailing genomic characteristics and delineating features of these tumors are available, often resulting in suboptimal treatment. Here, we explore the clinical, histopathologic, genomic features and potential therapies of five rare pulmonary tumors, namely adenosquamous, basaloid squamous, mucoepidermoid, carcinosarcoma, and NUT carcinoma, to build a resource for rare histological subtypes of the lung and emphasize knowledge gaps in the management of these tumors. Our recommendations are based on a comprehensive review of case reports and series, clinical trials, and the "Indiana University Experience."

PMID:39731864 | DOI:10.1016/j.lungcan.2024.108035

Genet Med. 2024 Dec 24:101350. doi: 10.1016/j.gim.2024.101350. Online ahead of print.

ABSTRACT

PURPOSE: Genomic sequencing of newborns (NBSeq) can initiate disease surveillance and therapy for children, and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and had a risk for autosomal dominant disease identified.

METHODS: We conducted semi-structured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely-pathogenic (P/LP) variant associated with an autosomal dominant (AD) childhood- and/or adult-onset disease returned. We utilized directed content analysis to derive themes.

RESULTS: From 11 families, all first-degree relatives (n=32, 100%), 29 second-degree relatives (SDRs) (76%), and 26 third-degree relatives (TDRs) (43%) were informed of their risk. All parents (n=22, 69% of FDRs), four (11%) SDRs, and 1 (2%) TDR underwent cascade testing. Most parents preferred to handle risk communication themselves. Parents with positive cascade testing but no associated symptoms were less inclined to share findings with relatives, but highly motivated to share results if the variant's associated disease severity was high, as perceived with adult-onset conditions. One new subtheme, "family member traits," was identified and defined as a relative's propensity to anxiety/concern following risk communication, but did not diminish risk communication.

CONCLUSION: Findings can inform more effective notification and testing practices for families of newborns at risk for hereditary genetic conditions.

PMID:39731470 | DOI:10.1016/j.gim.2024.101350

BMJ Case Rep. 2024 Dec 27;17(12):e262395. doi: 10.1136/bcr-2024-262395.

ABSTRACT

Alkaptonuria is a rare inherited disease resulting from a genetic variant leading to homogentisic acid accumulation in body tissues, causing a broad spectrum of symptoms. Our case involves a Caucasian male diagnosed in his 70s, who shares a constellation of symptoms and the diagnosis with his monozygotic twin brother. The symptoms include early-onset arthropathy, tendinopathy, osteopenia, discolouration of the auricular regions and fingers, scleral discolouration, secondary glaucoma, proteinuria, calcification of the mitral valve and black urethral and prostate stones. Additionally, the patient suffers from chronic cough, polyneuropathy and corpus cysts in the thoracic spine have been found. This case highlights the importance of holistic assessments, recognition of familial symptom patterns and early identification of key clinical indicators for rare disease diagnosis. It also underscores the challenge of differentiating rare symptomatic manifestations from those unrelated to alkaptonuria.

PMID:39730168 | DOI:10.1136/bcr-2024-262395

PLoS One. 2024 Dec 26;19(12):e0309205. doi: 10.1371/journal.pone.0309205. eCollection 2024.

ABSTRACT

Rare diseases affect 1-in-10 people in the United States and despite increased genetic testing, up to half never receive a diagnosis. Even when using advanced genome sequencing platforms to discover variants, if there is no connection between the variants found in the patient's genome and their phenotypes in the literature, then the patient will remain undiagnosed. When a direct variant-phenotype connection is not known, putting a patient's information in the larger context of phenotype relationships and protein-protein interactions may provide an opportunity to find an indirect explanation. Databases such as STRING contain millions of protein-protein interactions, and the Human Phenotype Ontology (HPO) contains the relations of thousands of phenotypes. By integrating these networks and clustering the entities within, we can potentially discover latent gene-to-phenotype connections. The historical records for STRING and HPO provide a unique opportunity to create a network time series for evaluating the cluster significance. Most excitingly, working with Children's Hospital Colorado, we have provided promising hypotheses about latent gene-to-phenotype connections for 38 patients. We also provide potential answers for 14 patients listed on MyGene2. Clusters our tool finds significant harbor 2.35 to 8.72 times as many gene-to-phenotype edges inferred from known drug interactions than clusters found to be insignificant. Our tool, BOCC, is available as a web app and command line tool.

PMID:39724242 | DOI:10.1371/journal.pone.0309205

Hum Gene Ther. 2024 Dec 26. doi: 10.1089/hum.2024.175. Online ahead of print.

ABSTRACT

Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 (ABCD1) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG-hABCD1 vector injected intravenously in the neonatal period prevented the disease in 2-year-old Abcd1-/- mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of Abcd1-/- mice start losing balance and motricity. As soon as 1-3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice (n = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice (n = 34). In five white matter regions of the cervical spinal cord, hABCD1 expression at 24 months of age was present in 22% (18-27) of oligodendrocytes (OLs) and 22% (17-26) of astrocytes and not detected in neurons or microglia. Abundant hABCD1 expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG-hABCD1 vector at an early symptomatic stage of the Abcd1-/- mouse model paves a new oligotropic way for the gene therapy of AMN.

PMID:39723977 | DOI:10.1089/hum.2024.175

Orphanet J Rare Dis. 2024 Dec 23;19(1):485. doi: 10.1186/s13023-024-03446-w.

ABSTRACT

BACKGROUND: The combination of high prices and uncertain effectiveness is a growing challenge in the field of orphan medicines, hampering health technology assessments. Hence, new methods for establishing price benchmarks might be necessary to support reimbursement negotiations. In this study, we applied several pricing models containing cost-based elements to the case of lumasiran for treating primary hyperoxaluria type 1.

METHODS: Price ranges were calculated by estimating minimum and maximum scenarios for four pricing models: Novel Cancer Pricing Model (NCP-model), AIM Model for Innovative Medicines (AIM-model), Discounted Cash Flow model (DCF-model), and the Real-Option Rate Of Return model (ROROR-model). Data was gathered from disease registries, scientific literature, Security and Exchange Committee filings, and expert opinion. A sensitivity analysis was performed to assess the parameters with the largest influence.

RESULTS: Outcomes resulting from the NCP-model ranged between €87,000 and €224,000 per patient per year, between €33,000 and €340,000 for the AIM-model, between €182,000 and €748,000 for the DCF-model, and between €81,000 and €273,000 for the ROROR-model.

CONCLUSION: Outcomes of the four pricing models show wide and heterogeneous price ranges. The DCF-model might be most compatible with the case of lumasiran, due to inclusion of parameters for prevalence, incidence, prescription restrictions and cost of capital. The minimum DCF price could serve as a starting point for pricing and reimbursement negotiations. Uncertainties can be solved by more transparency on input variables.

PMID:39716306 | DOI:10.1186/s13023-024-03446-w

bioRxiv [Preprint]. 2024 Dec 9:2024.12.05.627004. doi: 10.1101/2024.12.05.627004.

ABSTRACT

Dystrophin-deficient zebrafish larvae are a small, genetically tractable vertebrate model of Duchenne muscular dystrophy well suited for early stage therapeutic development. However, current approaches for evaluating their impaired mobility, a physiologically relevant therapeutic target, are characterized by low resolution and high variability. To address this, we used high speed videography and deep learning-based markerless motion capture to develop linked-segment models of larval escape response (ER) swimming. Kinematic models provided repeatable, high precision estimates of larval ER performance. Effect sizes for ER peak instantaneous acceleration and speed, final displacement, and ER distance were 2 to 3.5 standard deviations less for dystrophin-deficient mutants vs. wild-types. Further analysis revealed that mutants swam slower because of a reduction in their tail stroke frequency with little change in tail stroke amplitude. Kinematic variables were highly predictive of the dystrophic phenotype with ≤ 3% of larvae misclassified by random forest and support vector machine models. Tail kinematics also performed as well as in vitro assessments of tail muscle contractility in classifying larvae as mutants or wild-type, suggesting that ER kinematics could serve as a non-lethal proxy for direct measurements of muscle function. In summary, ER kinematics can be used as precise, physiologically relevant, non-lethal biomarkers of the dystrophic phenotype. The open-source approach described here may have applications not only for studies of skeletal muscle disease but for other disciplines that use larval mobility as an experimental outcome.

PMID:39713379 | PMC:PMC11661059 | DOI:10.1101/2024.12.05.627004

Trials. 2024 Dec 21;25(1):845. doi: 10.1186/s13063-024-08678-6.

ABSTRACT

INTRODUCTION: The clinical, research and advocacy communities for Rett syndrome are striving to achieve clinical trial readiness, including having fit-for-purpose clinical outcome assessments. This study aimed to (1) describe psychometric properties of clinical outcome assessment for Rett syndrome and (2) identify what is needed to ensure that fit-for-purpose clinical outcome assessments are available for clinical trials.

METHODS: Clinical outcome assessments for the top 10 priority domains identified in the Voice of the Patient Report for Rett syndrome were compiled and available psychometric data were extracted. The clinical outcome assessments measured clinical severity, functional abilities, comorbidities and quality of life, and electrophysiological biomarkers. An international and multidisciplinary panel of 29 experts with clinical, research, psychometric, biostatistical, industry and lived experience was identified through International Rett Syndrome Foundation networks, to discuss validation of the clinical outcome assessments, gaps and next steps, during a workshop and in a follow-up questionnaire. The identified gaps and limitations were coded using inductive content analysis.

RESULTS: Variable validation profiles across 26 clinical outcome assessments of clinical severity, functional abilities, and comorbidities were discussed. Reliability, validity, and responsiveness profiles were mostly incomplete; there were limited content validation data, particularly parent-informed relevance, comprehensiveness and comprehensibility of items; and no data on meaningful change or cross-cultural validity. The panel identified needs for standardised administration protocols and systematic validation programmes.

CONCLUSION: A pipeline of collaborative clinical outcome assessment development and validation research in Rett syndrome can now be designed, aiming to have fit-for-purpose measures that can evaluate meaningful change, to serve future clinical trials and clinical practice.

PMID:39709426 | DOI:10.1186/s13063-024-08678-6

J Community Genet. 2024 Dec 21. doi: 10.1007/s12687-024-00763-2. Online ahead of print.

ABSTRACT

The European Reference Networks (ERNs) for rare and complex diseases offer significant potential for building, maintaining and evaluating patient partnership, for which the recently developed ERN Patient Partnership Framework may serve as guidance. This scoping review aims to identify and describe relevant frameworks published in scientific literature, capturing key learning points to inform future updates of the ERN Patient Partnership Framework and promote its use in practice. MEDLINE, Embase, and the Web of Science Core Collection were searched to identify recently published frameworks (2013-2023) focused on patient partnership and aligned with at least one core ERN activity. Framework characteristics were summarised and information pertaining to their content, structure and practical use was extracted. Twelve relevant frameworks were identified, presenting practical approaches, conceptual understandings or both. Five frameworks focused on areas aligned with specific core ERN activities; others had an overarching scope. Frameworks presented various engagement approaches and employed heterogeneous terminology and development methods. Frameworks differed in their content and structure and presented key considerations for use. Our review underscores the importance of providing clear definitions and explanations of patient partnership. It provides insight into how meaningful, and inclusive patient partnership can be promoted within our diverse ERN context and sheds light on the importance of framework implementation as a prerequisite to structured evaluation. Learning points generated from this review will be used to inform future updates of the ERN Patient Partnership Framework and promote its implementation in practice.

PMID:39708237 | DOI:10.1007/s12687-024-00763-2

Hastings Cent Rep. 2024 Dec;54 Suppl 2:S49-S55. doi: 10.1002/hast.4929.

ABSTRACT

The promise of genomic medicine lies in the opportunity to improve health outcomes via a personalized approach to management, grounded in genetic and genomic variation unique to an individual. However, disparities and inequities mar this remarkable landscape of genomic innovation. Prior efforts to understand these inequities have focused on populations for which genetic testing is relatively protocolized or where test utility varies greatly by ancestry groups, where equitable outcomes are more clearly defined. We therefore consider the current landscape of rare disease genomics, in which diagnostic approaches vary widely and utility remains to be fully understood, and suggest a path forward: how ecosocial theory may be used to guide novel equity-focused initiatives that incorporate illness narratives to improve population health. We present examples of narrative medicine in rare disease and reimagine the role this discipline may play in genomic sequencing studies, toward incorporation of the unique illness narrative into clinical genetics and genomics practice. Approaches that broaden the definitions of disease and of outcomes of interest will force the field to grapple with its racist history and begin to advance health equity and promote justice so that genomic medicine may truly deliver on its promise.

PMID:39707934 | DOI:10.1002/hast.4929

Med Sci (Paris). 2024 Dec;40(12):914-924. doi: 10.1051/medsci/2024181. Epub 2024 Dec 20.

ABSTRACT

The development of sequencing technologies and their increased accessibility in clinical services and genetic laboratories have considerably accelerated the identification of genetic variants associated with rare diseases (RDs). Among these, Mendelian disorders of the epigenetic machinery (MDEM) are rare monogenic diseases characterized by the presence of mutations in genes encoding epigenetic regulators that play a key role in organismal development and cellular functions. Loss of function of these regulators is expected to lead to epigenetic modifications that profoundly affect genome expression and cellular identity. Disruptions in DNA methylation profiles have been documented in MDEMs, emerging as a useful diagnostic tool. The current challenge is to determine whether and how these epigenomic alterations drive the mechanisms underlying the clinical manifestations in patients suffering from this class of diseases. Studying MDEMs may therefore shed light on the important role of epigenetic information in health and disease, particularly the mechanisms involved in the development and understanding of complex pathologies, such as neurodevelopmental disorders and cancer.

PMID:39705562 | DOI:10.1051/medsci/2024181

Orphanet J Rare Dis. 2024 Dec 19;19(1):467. doi: 10.1186/s13023-024-03482-6.

ABSTRACT

BACKGROUND: The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.

METHODS: Multi-stakeholder sessions covered the topics: Future Educational System, Randomization in Rare Disease Clinical Trials, Endpoints in Rare Disease Clinical Trials and Using History Course Data. The sessions began with expert presentations to set the scene, followed by guided discussions facilitated by questions on a collaborative digital whiteboard. Participants wrote responses, which were then discussed live with the experts.

RESULTS: Training is needed for diverse stakeholders in rare disease clinical trials to enhance understanding and drive innovation. Challenges include a lack of standardized terminology for multiple endpoints, inadequate understanding of randomization in small sample studies and various obstacles in effectively using natural history data.

CONCLUSION: Creating a comprehensive and sustainable educational program for rare diseases clinical trial methodology requires strategic collaboration and adherence to FAIR principles. The workshop highlighted the need for innovations for topics in areas such as handling missing data, optimizing the extraction of information from small samples, remote endpoint measurement and new randomized inference techniques. Additionally, integrating innovations into tailored training programs is crucial for advancing the field.

PMID:39702219 | DOI:10.1186/s13023-024-03482-6

BMC Urol. 2024 Dec 19;24(1):267. doi: 10.1186/s12894-024-01665-8.

ABSTRACT

A phyllodes tumor (PT) is a biphasic fibroepithelial lesion that is most commonly found in breast tissue, whereas it is uncommon in ureter tissue. Only one case has been documented so far. There are some similarities in histology and clinical characteristics between this type of tumor and PT of the female breast: the lesions can be surgically removed, but some recur locally and invade directly into the breast. This case of a primary PT of the ureter is useful for pathologists and clinicians.

PMID:39702215 | DOI:10.1186/s12894-024-01665-8

Comput Biol Med. 2025 Feb;185:109560. doi: 10.1016/j.compbiomed.2024.109560. Epub 2024 Dec 18.

ABSTRACT

BACKGROUND: Interpreting the pathogenicity of genetic variants associated with rare diseases is a laborious and time-consuming endeavour. To streamline the diagnostic process and lighten the burden of variant interpretation, it is crucial to automate variant annotation and prioritization. Unfortunately, currently available variant interpretation tools lack a unified and comprehensive workflow that can collectively assess the clinical significance of these types of variants together: small nucleotide variants (SNVs), small insertions/deletions (INDELs), copy number variants (CNVs) and structural variants (SVs).

RESULTS: The Unified Variant Interpretation Platform (UniVar) is a free web server tool that offers an automated and comprehensive workflow on annotation, filtering and prioritization for SNV, INDEL, CNV and SV collectively to identify disease-causing variants for rare diseases in one interface, ensuring accessibility for users even without programming expertise. To filter common CNVs/SVs, a diverse SV catalogue has been generated, that enables robust filtering of common SVs based on population allele frequency. Through benchmarking our SV catalogue, we showed that it is more complete and accurate than the state-of-the-art SV catalogues. Furthermore, to cope with those patients without detailed clinical information, we have developed a novel computational method that enables variant prioritization from gene panels. Our analysis shows that our approach could prioritize pathogenic variants as effective as using HPO terms assigned by clinicians, which adds value for cases without specific clinically assigned HPO terms. Lastly, through a practical case study of disease-causing compound heterozygous variants across SNV and SV, we demonstrated the uniqueness and effectiveness in variant interpretation of UniVar, edging over any existing interpretation tools.

CONCLUSIONS: UniVar is a unified and versatile platform that empowers researchers and clinicians to identify and interpret disease-causing variants in rare diseases efficiently through a single holistic interface and without a prerequisite for HPO terms. It is freely available without login and installation at https://univar.live/.

PMID:39700857 | DOI:10.1016/j.compbiomed.2024.109560

Neurology. 2025 Jan 14;104(1):e210106. doi: 10.1212/WNL.0000000000210106. Epub 2024 Dec 19.

ABSTRACT

BACKGROUND AND OBJECTIVES: Hypotonia is a relatively common finding among infants in the neonatal intensive care unit (NICU). Consideration of genetic testing is recommended early in the care of infants with unexplained hypotonia. We aimed to assess the diagnostic yield and overall impact of exome and genome sequencing (ES and GS).

METHODS: Consecutive infants with hypotonia were identified from research and clinical databases across 5 teaching hospitals in United States, Canada, United Kingdom, and Australia. Inclusion criteria included NICU admission and genetic evaluation. Infants with a known explanation for hypotonia were excluded. Data regarding infant characteristics, genetic testing, and diagnoses were collected. The primary outcome was identification of a molecular diagnosis. Impact on care was a secondary outcome. The Fisher exact and Wilcoxon rank-sum tests were used for statistical analysis.

RESULTS: We identified 147 infants with unexplained hypotonia. The median gestational age was 39 weeks (interquartile range [IQR] 36-42 weeks), 77 (52%) were female, and the median age was 8 days at the time of evaluation (IQR 2-19 days). Eighty (54%) had hypotonia as the main clinical feature while 67 (46%) had additional multisystem involvement. Seventy-five (51%) underwent rapid ES, 44 (30%) rapid GS, 2 (1%) both ES and GS, and 26 (18%) were admitted before ES or GS became available. Of the 121 infants who underwent ES and/or GS, 72 (60%) had the primary outcome of a molecular diagnosis. In addition, 2 infants with mitochondrial genome variants were diagnosed by mitochondrial GS after negative ES, and one infant needed targeted testing to identify a short tandem repeat expansion missed by GS. The proportion diagnosed by ES and GS was not different between infants with hypotonia as the primary finding (37/56, 66%) and infants with multisystemic symptoms (35/65, 54%, odds ratio [OR] 1.7, CI 0.8-3.7, p value = 0.20). Testing was more likely to have an impact on care for infants receiving a genetic diagnosis (57/66 vs 14/33, OR 8.4, CI 2.9-26.1, p = 1.0E-05).

DISCUSSION: Rapid ES and GS provided a molecular diagnosis for most of the infants with unexplained hypotonia who underwent testing. Further studies are needed to assess the generalizability of these findings as increased access to genetic testing becomes available.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in unexplained neonatal hypotonia, rapid ES or GS adds diagnostic specificity.

PMID:39700446 | DOI:10.1212/WNL.0000000000210106