Bone Marrow Transplant. 2022 Oct 13. doi: 10.1038/s41409-022-01837-w. Online ahead of print.

ABSTRACT

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology-COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators.

PMID:36229646 | DOI:10.1038/s41409-022-01837-w

JAMA Health Forum. 2021 Oct 1;2(10):e213467. doi: 10.1001/jamahealthforum.2021.3467.

ABSTRACT

IMPORTANCE: Although considered a rare disease with fewer than 200 000 cases annually in the US, sickle cell disease (SCD) is the most common and clinically significant inherited blood disorder in the US and worldwide. Despite the relatively high prevalence of this rare disease, there is a paucity of longitudinal data available to evaluate access to care or to identify quality metrics.

OBSERVATIONS: This review discusses why systematic data collection for SCD through population-wide surveillance programs can help to facilitate progress in treatment. It also explores the importance of having both a longitudinal clinical registry and a national surveillance program to improve resource utilization, clinical outcomes, and provide an equitable foundation for care.

CONCLUSIONS AND RELEVANCE: Federal funding should be appropriately allocated to establish and maintain a national SCD surveillance system supported by the Centers for Disease Control and Prevention, as well as a longitudinal registry available at recognized sickle cell centers.

PMID:36218900 | DOI:10.1001/jamahealthforum.2021.3467

BMJ Open. 2022 Oct 10;12(10):e061468. doi: 10.1136/bmjopen-2022-061468.

ABSTRACT

INTRODUCTION: Despite the superior diagnostic performance of exome and genome sequencing compared with conventional genetic tests, evidence gaps related to clinical utility and cost effectiveness have limited their availability in routine clinical practice in many jurisdictions. To inform adoption and reimbursement policy, this protocol provides a chain of evidence approach to determining the diagnostic utility, clinical utility and cost-effectiveness of whole exome sequencing (WES) from seven medical genetic centres in two Canadian provinces.

METHODS AND ANALYSIS: Using a multicentre observational cohort design, we will extract data specific to the pre-WES diagnostic pathway and 1-year post-WES medical management from electronic medical records for 650 patients with rare disease of suspected genetic aetiology who receive WES. The date from the clinical record will be linked to provincial administrative health database to capture healthcare resource use and estimate costs. Our analysis will: (1) define and describe diagnostic testing pathways that occur prior to WES among patients with rare disease, (2) determine the diagnostic utility of WES, characterised as the proportion of patients for whom causative DNA variants are identified, (3) determine the clinical utility of WES, characterised as a change in medical management triggered by WES results, (4) determine the pattern and cost of health service utilisation prior and 1 year following WES among patients who receive a diagnosis, do not receive a diagnosis, or receive an uncertain diagnosis and (5) estimate the cost-effectiveness of WES compared with conventional diagnostic testing pathways, measured by the incremental cost per additional patient diagnosed by WES using simulation modelling.

ETHICS AND DISSEMINATION: This protocol was approved by Clinical Trials Ontario (CTO-1577) and research ethics boards at the University of Calgary (REB18-0744 and REB20-1449) and University of Alberta (Pro0009156). Findings will be disseminated through academic publications and policy reports.

PMID:36216418 | DOI:10.1136/bmjopen-2022-061468

Front Immunol. 2022 Sep 22;13:922752. doi: 10.3389/fimmu.2022.922752. eCollection 2022.

ABSTRACT

Tremendous progress has been made in the recognition of primary immune deficiencies (PIDs) in Bulgaria since in 2005 we have joined the J Project Central-Eastern European collaborative program. Ten years later an Expert Centre (ExpC) for Rare Diseases - Primary Immune Deficiencies at the University Hospital "Alexandrovska"- Sofia was established. In May 2017 The National Register of Patients with Rare Diseases also became operational as a database containing clinical and genetic information for Bulgarian patients with PID. The transfer of data and information on Bulgarian PID patients to the European Primary Immunodeficiency Database, managed by the European Society for Primary Immunodeficiency (ESID) has started in 2020. The total number of registered patients now is 191 (100 men and 91 women), with more than half of them being children (106; 55.5%). Regular updating of the information in the register showed that 5.2% of patients are deceased and the majority (94.8%) is a subject to continuous monitoring as it has been reported for other European countries as well. With the establishment of the ExpC, the dynamics in the diagnosis and registration of patients with PID significantly intensified. For a period of 5 years (2016-2021) 101 patients were evaluated and registered in comparison with previous period - before ExpC establishment when only 89 patients were diagnosed. The most common pathology was humoral immune deficiency (85 patients; 44.5%). Ninety-six (50.3%) of the patients underwent genetic testing, and 66. 7% had genetically confirmed diagnosis. Three of the variants have not been reported in population databases. Following genetic investigation confirmation of the initial phenotypic diagnosis was achieved in 82.8% of cases and change in the diagnosis - in 17%. Sixty-two patients were on regular replacement or specific therapy, and the rest received symptomatic and supportive treatment. In summary, we present the first epidemiological report of PIDs in Bulgaria, based on the National PID register. Data on the clinical, phenotypic and genetic characteristics of PID patients provided important information about the nature of primary immunodeficiency diseases in our country.

PMID:36211402 | PMC:PMC9535737 | DOI:10.3389/fimmu.2022.922752

J Coll Physicians Surg Pak. 2022 Aug;32(8):S183-S185. doi: 10.29271/jcpsp.2022.Supp2.S183.

ABSTRACT

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. It is essential to gain a better understanding of the signs to clinically diagnose PAP and include PAP among the differential diagnoses of interstitial pulmonary diseases or other diseases with similar manifestations. We describe a 2.5-year patient with atopy who presented with pulmonary infiltration, recurrent wheezing, and cough despite steroid and salbutamol administration via inhalation. High-resolution computed tomography revealed crazy-paving patterns in both lungs, suggesting PAP. An open lung biopsy revealed intra-alveolar granular amphophilic material, which was strongly positive on periodic acid-Schiff staining. The results of pulmonary-associated surfactant protein B and C gene analyses were normal. However, granulocyte-macrophage colony-stimulating factor receptor beta-protein was not detected in leucocytes, and a novel mutation was identified in the CSF2RB gene. The patient was diagnosed with PAP and treated with whole-lung lavage. Key Words: Pulmonary alveolar proteinosis, Child, Atopy, Wheezing.

PMID:36210689 | DOI:10.29271/jcpsp.2022.Supp2.S183

J Coll Physicians Surg Pak. 2022 Aug;32(8):S147-S149. doi: 10.29271/jcpsp.2022.Supp2.S147.

ABSTRACT

Glucagonoma syndrome is an extremely rare paraneoplastic disorder. The key presenting feature is a rash (necrolytic migratory erythema) which can easily be misdiagnosed as a primary skin disorder. Moreover, 50 to 80 % of patients already have metastatic disease at diagnosis. We report a case of a 38-year female presenting with epigastric pain and a skin rash all over the body. Workup revealed a neuroendocrine tumor (NET) of the pancreas, for which she underwent resection, resulting in a complete cure. A follow-up MRI after 8 months showed a hyperintense and arterially enhancing nodular liver lesion which did not show any uptake on the octreotide scan. However, a subsequent biopsy revealed a recurrence of the tumor. This was a unique finding in our case where a highly sensitive octreotide scan failed to identify metastasis, emphasising the importance of biopsy in such cases. Key Words: Glucagonoma, Necrolytic migratory erythema, Alpha-cell adenom.

PMID:36210677 | DOI:10.29271/jcpsp.2022.Supp2.S147

Epilepsy Behav. 2022 Oct 7;136:108927. doi: 10.1016/j.yebeh.2022.108927. Online ahead of print.

ABSTRACT

Rare epilepsy centers, also called reference centers in France, have the mission to coordinate care for rare diseases, improve knowledge, and conduct research on rare diseases. Dissemination of knowledge is conducted in collaboration with patient associations. In just a few years, the Internet and social media have become the main source for news and knowledge. We conducted a survey about the use of social media and the expectations of patient associations from a rare epilepsy center. From the 29 associations on our website, 18 (62%) answered the survey, representing about 9000 members. All of the patient associations use social media. Facebook is used by all of them, and most of them also used additional social media channels. 13/18 (72%) associations found that it was easy to get in touch with our center and almost all partner associations were satisfied with the information published on our website (17/18, 94%). Eight patient associations (8/15, 53%) expected more information from us regarding scientific news (10/13) and clinical trials (8/13). Despite the existence of an active website and a monthly newsletter, the family associations interacting with our rare epilepsy center still want to collaborate even more with us. The use of social media by the rare epilepsy centers might help to fill the gap of the knowledge dissemination.

PMID:36215829 | DOI:10.1016/j.yebeh.2022.108927

J Transl Med. 2022 Oct 8;20(1):458. doi: 10.1186/s12967-022-03671-6.

ABSTRACT

BACKGROUND: The low number of patients suffering from any given rare diseases poses a difficult problem for medical research: With the exception of some specialized biobanks and disease registries, potential study participants' information are disjoint and distributed over many medical institutions. Whenever some of those facilities are in close proximity, a significant overlap of patients can reasonably be expected, further complicating statistical study feasibility assessments and data gathering. Due to the sensitive nature of medical records and identifying data, data transfer and joint computations are often forbidden by law or associated with prohibitive amounts of effort. To alleviate this problem and to support rare disease research, we developed the Mainzelliste Secure EpiLinker (MainSEL) record linkage framework, a secure Multi-Party Computation based application using trusted-third-party-less cryptographic protocols to perform privacy-preserving record linkage with high security guarantees. In this work, we extend MainSEL to allow the record linkage based calculation of the number of common patients between institutions. This allows privacy-preserving statistical feasibility estimations for further analyses and data consolidation. Additionally, we created easy to deploy software packages using microservice containerization and continuous deployment/continuous integration. We performed tests with medical researchers using MainSEL in real-world medical IT environments, using synthetic patient data.

RESULTS: We show that MainSEL achieves practical runtimes, performing 10 000 comparisons in approximately 5 minutes. Our approach proved to be feasible in a wide range of network settings and use cases. The "lessons learned" from the real-world testing show the need to explicitly support and document the usage and deployment for both analysis pipeline integration and researcher driven ad-hoc analysis use cases, thus clarifying the wide applicability of our software. MainSEL is freely available under: https://github.com/medicalinformatics/MainSEL CONCLUSIONS: MainSEL performs well in real-world settings and is a useful tool not only for rare disease research, but medical research in general. It achieves practical runtimes, improved security guarantees compared to existing solutions, and is simple to deploy in strict clinical IT environments. Based on the "lessons learned" from the real-word testing, we hope to enable a wide range of medical researchers to meet their needs and requirements using modern privacy-preserving technologies.

PMID:36209221 | PMC:PMC9547637 | DOI:10.1186/s12967-022-03671-6

Orphanet J Rare Dis. 2022 Oct 8;17(1):372. doi: 10.1186/s13023-022-02520-5.

ABSTRACT

BACKGROUND: Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system.

RESULTS: During the program (2018-2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration.

CONCLUSIONS: The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.

PMID:36209187 | PMC:PMC9548182 | DOI:10.1186/s13023-022-02520-5

Orphanet J Rare Dis. 2022 Oct 8;17(1):371. doi: 10.1186/s13023-022-02534-z.

ABSTRACT

OBJECTIVE: Rare diseases are life-threatening, debilitating, or serious chronic conditions that affect < 50/100,000 people. Canadians can only access approximately 60% of drugs for rare diseases (DRDs), which is partially related to high per-patient costs and payers' affordability concerns. However, limiting access to DRDs can reduce survival and quality of life among patients and caregivers. Therefore, we projected Canadian non-oncology DRD spending relative to total public drug spending to provide perspective for decision makers.

METHODS: Candidate historical (2010-2020) and pipeline (2021-2025) Canadian-marketed non-oncology DRDs were identified using definitions from the European Medicines Agency and the US Food and Drug Administration databases. Inclusion and exclusion criteria were applied to identify eligible DRDs. Public payer claims data, prevalence rates, regulatory, and health technology assessment factors were used to project DRD spending in relation to total Canadian public drug spending.

RESULTS: We included 42 historical DRDs and 122 pipeline DRDs. Public spending on DRDs grew from $14.8 million in 2010 (11 DRDs) to $380.9 million in 2020, then a projected $527.6 million in 2021 (59 potential DRDs) and $1.6 billion in 2025 (164 potential DRDs). Projected DRD spending increased from 3.2% of $16.5 billion public drug spending in 2021 to 8.3% of $19.4 billion in 2025. These projections do not include confidential manufacturer discounts, health outcome-related offsets, or additional safety-related costs.

CONCLUSIONS: Projected DRD spending shows robust growth but remains a fraction of total public drug spending. Limiting DRD access because of this growth is not aligned with Canadian patient or societal values. Given the renewed interest in a Canadian DRD framework, our results may help guide discussions that aim to balance control of public drug spending with the well-being of patients with rare diseases.

PMID:36209128 | PMC:PMC9548177 | DOI:10.1186/s13023-022-02534-z

Orphanet J Rare Dis. 2022 Oct 8;17(1):373. doi: 10.1186/s13023-022-02524-1.

ABSTRACT

BACKGROUND: Rare diseases impose a heavy economic burden on patients' families and society worldwide. This study used the samples from Sichuan Province in China to estimate the curative care expenditure (CCE) of ten rare diseases, for supporting the prioritization of rare disease health policies.

METHODS: Multi-stage cluster sampling method was adopted to investigate 9714 rare disease patients from 1556 medical institutions in Sichuan Province. Based on the System of Health Accounts 2011, this study estimated the total CCE of 10 rare diseases, financing schemes, and their allocation among different medical institutions and groups of people.

RESULTS: In 2018, the total CCE of the ten rare diseases was $19.00 million, the three costliest rare diseases were Hemophilia ($4.38 million), Young-onset Parkinson's disease ($2.96 million), and Systemic Sclerosis ($2.45 million). Household out-of-pocket expenditure (86.00% for outpatients, 41.60% for inpatients) and social health insurance (7.85% for outpatients; 39.58% for inpatients) were the main sources of financing CCE. The out-of-pocket expenditures for patients with Young-onset Parkinson's disease, Congenital Scoliosis, and Autoimmune Encephalitis accounted for more than 60% of the total CCE. More than 80% of the rare disease CCE was incurred in general hospitals. The 40-59 age group accounted for the highest CCE (38.70%) while men spent slightly more (55.37%) than women (44.64%).

CONCLUSIONS: As rare disease treatment is costly and household out-of-pocket expenditure is high, we suggest taking steps to include rare disease drugs in the National Reimbursement Drug List and scientifically re-design insurance coverage. It is also necessary to explore a multi-tiered healthcare security system to pay for the CCE of rare diseases and reduce the economic burden on patients.

PMID:36209113 | PMC:PMC9548194 | DOI:10.1186/s13023-022-02524-1

Vnitr Lek. 2022 Summer;68(E-2):11-21.

ABSTRACT

Langerhans cell histiocytosis (LCH) is a rare condition with incidence in adults 1-2/1 million, wherein Langerhans cells proliferate abnormally, adversely impacting organs including most frequently bones, skin, lungs, pituitary gland, lymph nodes, gums and other organs. The LCH course varies widely among patients from a self-limiting condition, to one that progresses. But LCH only very rarely culminates in death. To aim of this text is to review all possible symptoms and manifestations of this disease.

PMID:36208940

Nat Commun. 2022 Oct 7;13(1):5918. doi: 10.1038/s41467-022-33642-w.

ABSTRACT

Replication errors and various genotoxins cause DNA double-strand breaks (DSBs) where error-prone repair creates genomic mutations, most frequently focal deletions, and defective repair may lead to neurodegeneration. Despite its pathophysiological importance, the extent to which faulty DSB repair alters the genome, and the mechanisms by which mutations arise, have not been systematically examined reflecting ineffective methods. Here, we develop PhaseDel, a computational method to detect focal deletions and characterize underlying mechanisms in single-cell whole genome sequences (scWGS). We analyzed high-coverage scWGS of 107 single neurons from 18 neurotypical individuals of various ages, and found that somatic deletions increased with age and in highly expressed genes in human brain. Our analysis of 50 single neurons from DNA repair-deficient diseases with progressive neurodegeneration (Cockayne syndrome, Xeroderma pigmentosum, and Ataxia telangiectasia) reveals elevated somatic deletions compared to age-matched controls. Distinctive mechanistic signatures and transcriptional associations suggest roles for somatic deletions in neurodegeneration.

PMID:36207339 | DOI:10.1038/s41467-022-33642-w

J Invest Surg. 2022 Nov-Dec;35(11-12):1836-1840. doi: 10.1080/08941939.2022.2130481. Epub 2022 Oct 6.

ABSTRACT

INTRODUCTION: Splenic abscess secondary to endocarditis is a rare complication with high mortality. The treatment modality, splenectomy versus percutaneous drainage, and the best time, before or after valve replacement, are controversial. In the literature, there are only a few small case series about the subject. The objective of this study is to analyze the experience of a referral center in treating such condition.

METHODS: Patients with splenic abscesses due to endocarditis from 2006 to 2020 were retrospectively analyzed.

RESULTS: Thirteen patients (mean age 46 years old, 69% male) were identified. Eight patients (62%) had at least 2 comorbidities and 5 (38%) had a history of cardiac surgery. The diagnosis was incidental in 6 (46%). The mean time of abscess diagnosis after endocarditis definition was 14 days. Six patients (46%) had at least two organ dysfunctions. The median APACHE II score was 12 overall, and 24.5 in patients who died. Six patients (46%) had a valve replacement, and in two the abscess was diagnosed postoperatively. Of the other four patients, splenectomy was performed before the cardiac operation in three and at the same time in one. Splenectomy was performed immediately in 9 (69%) patients while three patients had percutaneous drainage (23%), one of which underwent splenectomy due to drainage failure. Exclusive antibiotic treatment was performed on only one patient. The median length of hospitalization was 24 days and mortality was 46%.

CONCLUSION: Splenic abscess due to endocarditis is a life-threatening condition with controversial treatment that results in a prolonged length of stay and high mortality.

PMID:36202396 | DOI:10.1080/08941939.2022.2130481

J Eur Acad Dermatol Venereol. 2022 Oct 4. doi: 10.1111/jdv.18637. Online ahead of print.

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.

OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany.

METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories, and patient organization.

RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB, and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries.

CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

PMID:36196047 | DOI:10.1111/jdv.18637

Br J Dermatol. 2022 Oct;187(4):453-454. doi: 10.1111/bjd.21686.

NO ABSTRACT

PMID:36192346 | DOI:10.1111/bjd.21686

Neurology. 2022 Oct 4;99(14):e1511-e1526. doi: 10.1212/WNL.0000000000200927. Epub 2022 Jul 18.

ABSTRACT

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.

METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.

RESULTS: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.

DISCUSSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

PMID:36192182 | DOI:10.1212/WNL.0000000000200927

Genome Med. 2022 Sep 30;14(1):113. doi: 10.1186/s13073-022-01113-y.

ABSTRACT

BACKGROUND: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.

METHODS: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions.

RESULTS: We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A.

CONCLUSIONS: Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.

PMID:36180924 | PMC:PMC9526336 | DOI:10.1186/s13073-022-01113-y

Orphanet J Rare Dis. 2022 Sep 29;17(1):366. doi: 10.1186/s13023-022-02458-8.

ABSTRACT

BACKGROUND: Rare diseases are a new global health priority, requiring evidence-based estimates of the global prevalence of diseases to inform public policymakers and provide a serious challenge to the healthcare system that must not be ignored. The purpose of this study is to investigate Iranian future healthcare professionals' knowledge and opinions about rare diseases.

RESULTS: A total of 6838 students responded to the questionnaire. Nursing and medical students had the highest participation. Almost 85% of participants rated their knowledge about rare diseases as poor or insufficient. While nearly 70 percent of participants took courses about rare diseases at university. Finally, 72.7% of future healthcare professionals did not feel ready to take care of a patient with a rare disease.

CONCLUSION: The present study has indicated a gap in Iranian medical students' knowledge of rare diseases. The researchers believe that health science policymakers should make a joint effort to improve knowledge about rare diseases. Including courses with regard to rare diseases would be of benefit to future healthcare professionals.

PMID:36175905 | PMC:PMC9524105 | DOI:10.1186/s13023-022-02458-8

BMJ Case Rep. 2022 Sep 29;15(9):e249986. doi: 10.1136/bcr-2022-249986.

ABSTRACT

Incarceration of the gravid uterus (IGU) is a rare obstetric disorder that may lead to pregnancy-related complications. Acute urinary retention (AUR) is one of the associated symptoms in IGU and it is mostly observed in the first semester and early second trimester. A case of a woman, in her 30s, is described, who presented AUR and lower abdominal pain in the early second trimester. The diagnosis was confirmed upon pelvic examination, and abdominal and transvaginal ultrasound. Management included long-term bladder catheterisation, manual reduction manoeuvres and passive positioning manoeuvres at home. At 24 weeks of gestation, the uterus returned in its correct polarity, the Foley catheter was removed and the patient was able to void spontaneously. A healthy infant was delivered vaginally at term.No specific guidelines have been published for IGU treatment. However, prompt diagnosis and tight follow-up of these patients are essential to define strategies, reduce complications and prevent recurrences.

PMID:36175041 | DOI:10.1136/bcr-2022-249986