PLoS One. 2023 Jul 28;18(7):e0289346. doi: 10.1371/journal.pone.0289346. eCollection 2023.

ABSTRACT

The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at >1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though ~0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (<0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.

PMID:37506127 | PMC:PMC10381067 | DOI:10.1371/journal.pone.0289346

PLoS One. 2023 Jul 28;18(7):e0288875. doi: 10.1371/journal.pone.0288875. eCollection 2023.

ABSTRACT

Over half of all persons with rare diseases (RDs) in Spain experience diagnostic delay (DD) but little is known about its consequences. This study therefore aimed to analyze the psychological impact of obtaining a diagnosis of an RD, and to ascertain what social determinants are influenced and what the personal consequences are, according to whether or not patients experienced DD. Data were obtained from a purpose-designed form completed by persons registered at the Spanish Rare Diseases Patient Registry. The following were performed: a descriptive analysis; a principal component analysis (PCA); and logistic regressions. Results revealed that while searching for a diagnosis, people who experienced DD were more in need of psychological care than those diagnosed in less than one year (36.2% vs 23.2%; p = 0.002; n = 524). The PCA identified three principal components, i.e., psychological effects, social implications, and functional impact. Reducing DD would improve psychological effects, such as irritability (OR 3.6; 95%CI 1.5-8.5), frustration (OR 3.4; 95%CI 1.7-7.1) and concentration on everyday life (OR 3.3; 95%CI 1.4-7.7). The influence of the social implications and functional repercussions of the disease was greater in persons with DD (scores of 22.4 vs 20 and 10.6 vs 9.4, respectively) in terms of the difficulty in explaining symptoms to close friends and family (3.3 vs 2.9), and loss of independence (3.3 vs 2.9). In conclusion, this is the first study to analyze the psychosocial impact of diagnosis of RDs in Spain and one of few to assess it in the patients themselves, based on data drawn from a purpose-designed form from a national registry open to any RD. People affected by RDs who underwent DD experienced greater psychosocial impact than did those who were diagnosed within the space of one year.

PMID:37506095 | PMC:PMC10381039 | DOI:10.1371/journal.pone.0288875

J Clin Immunol. 2023 Jul 29. doi: 10.1007/s10875-023-01554-z. Online ahead of print.

ABSTRACT

PURPOSE: Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3-/+) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3-/+ early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3-/+ from AD.

METHODS: This multicenter study involved 100 patients with DOCK8-/- and STAT3-/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8-/- or STAT3-/+ from AD.

RESULTS: There were 43 patients with DOCK8-/-, 23 with STAT3-/+, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3-/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3-/+ and AD via PCA.

CONCLUSIONS: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.

PMID:37507632 | DOI:10.1007/s10875-023-01554-z

medRxiv. 2023 Jul 13:2023.07.11.23292522. doi: 10.1101/2023.07.11.23292522. Preprint.

ABSTRACT

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance, and that taxanes are effective in the treatment of other gastrointestinal tumors including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.3 months. Of 10 evaluable patients we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.

PMID:37502847 | PMC:PMC10370227 | DOI:10.1101/2023.07.11.23292522

J Inorg Biochem. 2023 Oct;247:112334. doi: 10.1016/j.jinorgbio.2023.112334. Epub 2023 Jul 19.

ABSTRACT

The deregulation of copper homoeostasis can promote various diseases such as Menkes disease or hypertrophic cardioencephalomyopathy. We have recently synthesized solid copper(II) complexes ([Cu(His)2Cl2] and [Cu(Ser)2]), stable in physiological media and with potential as therapeutic agents. This report describes: i) the biocompatibility of these complexes at concentrations up to 100 μM using a differentiated Caco-2 cells model; ii) their transport across the intestinal epithelium using a transepithelial resistance assay and monitoring the amount of copper complexes at the apical and basolateral sides of the cells. The results suggest that the flow occurs through paracellular routes. The intracellular copper retention was <2.7% with no significant differences in intracellular copper content between 6 h and 48 h, suggesting an early copper retention process. Furthermore, this is the first evidence that demonstrates [Cu(His)2Cl2] and [Cu(Ser)2] induce transcriptional downregulation of the four major copper transporters (CTR1, DMT1, ATP7A, ATP7B), and the upregulation of the metallothionein gene expression. A remarkable finding was the increase in cytochrome c oxidase activity observed after the treatment of differentiated Caco-2 cells with copper(II) complexes at concentrations of 50-100 μM. The understanding of the transport mechanisms of these copper(II) complexes across the intestinal epithelium and of their subsequent biological activities could contribute to the development of optimal pharmaceutical formulations for the therapy of copper deficiency-related diseases.

PMID:37499466 | DOI:10.1016/j.jinorgbio.2023.112334

Orphanet J Rare Dis. 2023 Jul 27;18(1):216. doi: 10.1186/s13023-023-02823-1.

ABSTRACT

BACKGROUND: Rare diseases (RDs) affect approximately 8% of all people or > 400 million people globally. The Australian Government's National Strategic Action Plan for Rare Diseases has identified the need for a national, coordinated, and systematic approach to the collection and use of RD data, including registries. Rare disease registries (RDRs) are established for epidemiological, quality improvement and research purposes, and they are critical infrastructure for clinical trials. The aim of this scoping review was to review literature on the current state of RDRs in Australia; to describe how they are funded; what data they collect; and their impact on patient outcomes.

METHODS: We conducted a literature search on MEDLINE, EMBASE, CINAHL and PsychINFO databases, in addition to Google Scholar and grey literature. Dissertations, government reports, randomised control trials, conference proceedings, conference posters and meeting abstracts were also included. Articles were excluded if they did not discuss RDs or if they were written in a language other than English. Studies were assessed on demographic and clinical patient characteristics, procedure or treatment type and health-related quality of life captured by RDRs or databases that have been established to date.

RESULTS: Seventy-four RDRs were identified; 19 were global registries in which Australians participated, 24 were Australian-only registries, 10 were Australia and New Zealand based, and five were Australian jurisdiction-based registries. Sixteen "umbrella" registries collected data on several different conditions, which included some RDs, and thirteen RDRs stored rare cancer-specific information. Most RDRs and databases captured similar types of information related to patient characteristics, comorbidities and other clinical features, procedure or treatment type and health-related quality of life measures. We found considerable heterogeneity among existing RDRs in Australia, especially with regards to data collection, scope and quality of registries, suggesting a national coordinated approach to RDRs is required.

CONCLUSION: This scoping review highlights the current state of Australian RDRs, identifying several important gaps and opportunities for improvement through national coordination and increased investment.

PMID:37501152 | PMC:PMC10373259 | DOI:10.1186/s13023-023-02823-1

Orphanet J Rare Dis. 2023 Jul 27;18(1):220. doi: 10.1186/s13023-023-02684-8.

ABSTRACT

OBJECTIVES: Rare diseases are a global public health issue with a more pressing situation in China. Unfortunately, the relevant research and development in this country are still in its infancy, leading to limited drug accessibility. In view of this, the Chinese government has taken a series of countermeasures to promote orphan drug R&D in recent years, which has presented encouraging results. This paper aims to review incentive policies and funding initiatives formulated by the Chinese government and examine their implications on orphan drug R&D.

METHODS: Policies targeting orphan drug R&D during 2012-2022 were retrieved from the relevant official websites, categorized into different themes and analyzed for the contents. Data on government funding, drug approval, clinical trial approval and orphan drug designation were collected through internet search to analyze the implications of those incentive policies and initiatives on orphan drug R&D in China.

RESULTS: A total of 20 relevant policy documents were identified and five major themes were revealed through content analysis, including national strategy, expedited approval, safety and efficacy requirements, data protection and technical support. The government input in orphan drug R&D has witnessed a steady annual increase. Driven by those incentives, the numbers of orphan drugs approved for marketing and drug candidates entering clinical studies are increasing year by year, and more domestic pharmaceutical companies are actively involved in the R&D of orphan drugs.

CONCLUSIONS: Orphan drug development in China is growing rapidly under the stimulation of incentive regulatory policies and more investment in researches. China is working toward a more standardized and comprehensive rare disease ecosystem. However, there are still some challenges, such as the lack of sufficient financial support and the call for systematic legislation on rare diseases, to be addressed for future success.

PMID:37501126 | PMC:PMC10375655 | DOI:10.1186/s13023-023-02684-8

J Med Internet Res. 2023 Jul 27;25:e44641. doi: 10.2196/44641.

ABSTRACT

BACKGROUND: The minimum data set (MDS) is a collection of data elements to be grouped using a standard approach to allow the use of data for clinical and research purposes. Health data are typically voluminous, complex, and sometimes too ambiguous to generate indicators that can provide knowledge and information on health. This complexity extends further to the rare disease (RD) domain. MDSs are essential for health surveillance as they help provide services and generate recommended population indicators. There is a bottleneck in international literature that reveals a global problem with data collection, recording, and structuring in RD.

OBJECTIVE: This study aimed to identify and analyze the MDSs used for RD in health care networks worldwide and compare them with World Health Organization (WHO) guidelines.

METHODS: The population, concept, and context methodology proposed by the Joanna Briggs Institute was used to define the research question of this systematic review. A total of 4 databases were reviewed, and all the processes were reported using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. The data elements were analyzed, extracted, and organized into 10 categories according to WHO digital health guidelines. The quality assessment used the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist.

RESULTS: We included 20 studies in our review, 70% (n=14) of which focused on a specific health domain and 30% (n=6) of which referred to RD in general. WHO recommends that health systems and networks use standard terminology to exchange data, information, knowledge, and intelligence in health. However, there was a lack of terminological standardization of the concepts in MDSs. Moreover, the selected studies did not follow the same standard structure for classifying the data from their MDSs. All studies presented MDSs with limitations or restrictions because they covered only a specific RD, or their scope of application was restricted to a specific context or geographic region. Data science methods and clinical experience were used to design, structure, and recommend a fundamental global MDS for RD patient records in health care networks.

CONCLUSIONS: Our study highlights the difficulties in standardizing and categorizing findings from MDSs for RD because of the varying structures used in different studies. The fundamental RD MDS designed in this study comprehensively covers the data needs in the clinical and management sectors. These results can help public policy makers support other aspects of their policies. We highlight the potential of our results to help strategic decisions related to RD.

TRIAL REGISTRATION: PROSPERO CRD42021221593; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=221593.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.procs.2021.12.034.

PMID:37498666 | DOI:10.2196/44641

Orphanet J Rare Dis. 2023 Jul 25;18(1):213. doi: 10.1186/s13023-023-02820-4.

ABSTRACT

BACKGROUND: Rare diseases (RDs) are life-threatening or chronically debilitating and offer a high level of complexity. The aim of this study is to assess medical students' knowledge and awareness of RDs as well as their perceptions of potential measures to boost training in RDs. The cross-sectional survey was conducted at the Medical University of Plovdiv, Bulgaria, in 2019. The questionnaire contained 12 questions, divided into three main categories: (1) sociodemographic profile; (2) knowledge and awareness of RDs; and (3) attitudes about potential measures to improve training in RDs.

RESULTS: A total of 1189 medical students completed the survey with an overall response rate of 56.4%. Only 13% of participants knew the correct definition of RDs, and a low overall level of awareness was found with regard to orphan drugs (20.3%) and genetic counselling and testing (0.5%). Respondents believed that society as a whole was largely unaware of RDs as a major public health issue. Students suggested elective courses, and invited lectures by RDs experts, and participation in research projects as the most preferred measures to improve undergraduate training.

CONCLUSIONS: It is crucial to address the gaps in medical students' knowledge and awareness of RDs. University curricula should consider incorporating different RDs training modalities. It is essential to encourage various stakeholders to play a more proactive role and to collaborate in these activities. Involvement of patient organisations and advocacy groups might enhance students' knowledge of the challenges faced by people with RDs. Not least, the media should be partners in this important endeavour as well.

PMID:37491304 | PMC:PMC10369688 | DOI:10.1186/s13023-023-02820-4

J Nepal Health Res Counc. 2023 Jul 20;20(4):1008-1012. doi: 10.33314/jnhrc.v20i4.4520.

ABSTRACT

Genodermatoses are group of genetic disorders that present with cutaneous manifestations. The exact prevalence on many of these conditions are unknown due to its rarity, need of specialized tests for diagnosis and lack of proper reporting system. Most of the patients are faced with life-long disability and associated stigma. There is a need for specialized centers for proper diagnosis of these conditions and a very elaborated yet simple reporting system in Nepal. These rare conditions should be kept in priority by the government in align with the sustainable development goals to ensure healthy-lives and promote well-being for all. A wider engagement of patient-led support groups might be useful in providing necessary information on the disease to the general population and alleviate the stigma associated with these diseases. Keywords: Epidermolysis bullosa; genodermatoses; rare diseases; Nepal.

PMID:37489694 | DOI:10.33314/jnhrc.v20i4.4520

Indian J Pediatr. 2023 Jul 24. doi: 10.1007/s12098-023-04740-4. Online ahead of print.

ABSTRACT

OBJECTIVES: To estimate the economic burden of patients diagnosed with Gaucher disease at a public hospital from a societal perspective.

METHODS: Data from 30 Gaucher patients visiting the Genetic Clinic of the Department of Pediatrics at the study site in Mumbai was analyzed between January 2019 and January 2021. A cost of illness analysis was undertaken to estimate direct, indirect and intangible costs. Costs in treated and treatment naive groups were compared.

RESULTS: The total cost (direct and indirect) for 30 patients was ₹25,45,74,743/- (3440199.2 USD). Majority of this cost (99.8%) was due to direct costs of which medications [Enzyme replacement therapy (ERT) and Substrate reduction therapy (SRT)] constituted 98.8%. The notional cost was ₹1,43,94,695. Total costs of 14 treated patients were ₹25,29,67,279 and 16 treatment naive patients were ₹16,15,064 with a ratio of 157:1. Direct costs and cost of school absenteeism were significantly higher in the treated subgroup. Overall, direct, total costs and costs of school absenteeism were significantly associated with age and disease duration.

CONCLUSIONS: The economic burden of Gaucher disease is a staggering amount. This is an underestimate, as the expenses are highly subsidized in a public health facility. The highest contributor to cost component was direct costs, especially medication costs. Against the backdrop of the National Policy for Rare Diseases, resource allocation towards Gaucher disease should consider short term measures for judicious funding or reimbursement of disease-specific therapy and long-term cost-effective measures for promoting preventive strategies as the most practically feasible solution to reduce this economic burden.

PMID:37486590 | DOI:10.1007/s12098-023-04740-4

Heliyon. 2023 Jun 5;9(6):e17005. doi: 10.1016/j.heliyon.2023.e17005. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a serious autosomal recessive disorder. Early diagnosis, comorbidity prevention, and control are cornerstones for a quality life and for improving life expectancy. In Colombian Caribbean, where there is a genetically admixed population, CF is an orphan disease affecting children and adults, and it remains a challenging issue to be addressed carefully. This work describes the genetic, clinical, and paraclinical profiles of CF patients from Cartagena de Indias, Colombia.

METHODS: Thirty-six patients were included in the study. The subjects were identified and evaluated through the Regional Program for CF patients. CFTR gene mutations, anthropometric parameters, microbiological infections, and pulmonary function were analyzed. Data on demographic parameters, pharmacological treatments, and comorbidities were reported. Frequency and percentages were established for the categorical variables and mean or median for the quantitative variables. In addition, comparisons were made by sex.

RESULTS: The average age of the patients was 11.9 ± 5.3 years and the median age at diagnosis was 14 months. 55.5% were women and 44.5% were men. The mean values for weight, height, and body mass index were 35 ± 17.6 kg, 139.9 ± 28 cm, and 16.5 ± 2.9 kg/m2, respectively. The clinical manifestations that occurred more frequently were steatorrhea (65.4%) and recurrent pneumonia (46.2%). Chronic airway infection with Pseudomonas aeruginosa was identified in 71.4% of the cases and the p.F508del mutation was found in 47.2% of the subjects.

CONCLUSION: The current profile of CF patients from the Colombian Caribbean showed some concerning features, such as nutritional status; however, progress in early diagnosis and clinical follow-up could contribute to improve the general conditions of patients. It is necessary to continue efforts to increase the life expectancy and quality of life of the patients.

PMID:37484404 | PMC:PMC10361099 | DOI:10.1016/j.heliyon.2023.e17005

Orphanet J Rare Dis. 2023 Jul 21;18(1):196. doi: 10.1186/s13023-023-02776-5.

ABSTRACT

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS.

RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing.

CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

PMID:37480080 | PMC:PMC10360326 | DOI:10.1186/s13023-023-02776-5

Rev Neurol. 2023 Jul 28;77(s01):S3-S5. doi: 10.33588/rn.77s01.2023196.

ABSTRACT

INTRODUCTION: ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation) is a rare disease, with only about two hundred cases reported to date, that starts in previously healthy children. The first sign is usually obesity, followed by hypothalamic dysfunction and sleep-disordered breathing, which rapidly progresses until the death of the patient. ROHHAD with narcolepsy is even rarer, with only two cases described so far.

CASE REPORT: We report the case of a boy who showed signs of obesity and sleepiness since he was 5 years old. At the age of 7, he suffered two tonic-clonic seizures and, over the next four years, displayed signs and symptoms of significant hypothalamic dysfunction; after multiple tests, he was then diagnosed with ROHHAD. Despite receiving a large number of treatments, the patient died at the age of 11.

CONCLUSION: The pathophysiology of this disease needs to be clarified in order to investigate effective treatments in the future.

PMID:37477027 | DOI:10.33588/rn.77s01.2023196

Bioorg Med Chem. 2023 Sep 7;92:117375. doi: 10.1016/j.bmc.2023.117375. Epub 2023 Jun 8.

NO ABSTRACT

PMID:37474404 | DOI:10.1016/j.bmc.2023.117375

Genet Test Mol Biomarkers. 2023 Jul;27(7):203-204. doi: 10.1089/gtmb.2023.29074.persp. Epub 2023 Jul 20.

NO ABSTRACT

PMID:37471205 | DOI:10.1089/gtmb.2023.29074.persp

BMJ Paediatr Open. 2023 Jul;7(1):e002002. doi: 10.1136/bmjpo-2023-002002.

ABSTRACT

Inborn errors of immunity (IEI), also known as primary immunodeficiency diseases, comprise a group of rare genetic disorders that affect the development or/and function of the immune system. These disorders predispose individuals to recurrent infections, autoimmunity, cancer and immune dysregulations. The field of IEI diagnosis and treatment in mainland China has made significant strides in recent years due to advances in genome sequencing, genetics, immunology and treatment strategies. However, the accessibility and affordability of diagnostic facilities and precision treatments remain variable among different regions. With the increasing government emphasis on rare disease prevention, diagnosis, and treatment, the field of IEI is expected to progress further in mainland China. Herein, we reviewed the development and current state of IEI in mainland China, highlighting the achievements made, as well as opportunities and challenges that lie ahead.

PMID:37474202 | PMC:PMC10357751 | DOI:10.1136/bmjpo-2023-002002

JAMA Netw Open. 2023 Jul 3;6(7):e2324380. doi: 10.1001/jamanetworkopen.2023.24380.

ABSTRACT

IMPORTANCE: Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling.

OBJECTIVE: To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022.

EXPOSURES: Phenotypic features associated with diagnostic genetic results.

MAIN OUTCOMES AND MEASURES: Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported.

RESULTS: A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses.

CONCLUSIONS AND RELEVANCE: These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

PMID:37471090 | DOI:10.1001/jamanetworkopen.2023.24380

Bioinformatics. 2023 Jul 1;39(7):btad440. doi: 10.1093/bioinformatics/btad440.

ABSTRACT

MOTIVATION: Despite low prevalence, rare diseases affect 300 million people worldwide. Research on pathogenesis and drug development lags due to limited commercial potential, insufficient epidemiological data, and a dearth of publications. The unique characteristics of rare diseases, including limited annotated data, intricate processes for extracting pertinent entity relationships, and difficulties in standardizing data, represent challenges for text mining.

RESULTS: We developed a rare disease data acquisition framework using text mining and knowledge graphs and constructed the most comprehensive rare disease knowledge graph to date, Rare Disease Bridge (RDBridge). RDBridge offers search functions for genes, potential drugs, pathways, literature, and medical imaging data that will support mechanistic research, drug development, diagnosis, and treatment for rare diseases.

AVAILABILITY AND IMPLEMENTATION: RDBridge is freely available at http://rdb.lifesynther.com/.

PMID:37458501 | PMC:PMC10368801 | DOI:10.1093/bioinformatics/btad440

Rheumatol Int. 2023 Oct;43(10):1925-1934. doi: 10.1007/s00296-023-05372-9. Epub 2023 Jul 15.

ABSTRACT

Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.

PMID:37452880 | DOI:10.1007/s00296-023-05372-9