BMC Med Inform Decis Mak. 2021 Nov 16;21(Suppl 9):304. doi: 10.1186/s12911-021-01664-x.

ABSTRACT

BACKGROUND: The historical data of rare disease is very scarce in reality, so how to perform drug repositioning for the rare disease is a great challenge. Most existing methods of drug repositioning for the rare disease usually neglect father-son information, so it is extremely difficult to predict drugs for the rare disease.

METHOD: In this paper, we focus on father-son information mining for the rare disease. We propose GRU-Cooperation-Attention-Network (GCAN) to predict drugs for the rare disease. We construct two heterogeneous networks for information enhancement, one network contains the father-nodes of the rare disease and the other network contains the son-nodes information. To bridge two heterogeneous networks, we set a mapping to connect them. What's more, we use the biased random walk mechanism to collect the information smoothly from two heterogeneous networks, and employ a cooperation attention mechanism to enhance repositioning ability of the network.

RESULT: Comparing with traditional methods, GCAN makes full use of father-son information. The experimental results on real drug data from hospitals show that GCAN outperforms state-of-the-art machine learning methods for drug repositioning.

CONCLUSION: The performance of GCAN for drug repositioning is mainly limited by the insufficient scale and poor quality of the data. In future research work, we will focus on how to utilize more data such as drug molecule information and protein molecule information for the drug repositioning of the rare disease.

PMID:34789254 | PMC:PMC8596891 | DOI:10.1186/s12911-021-01664-x

Nat Commun. 2021 Nov 16;12(1):6618. doi: 10.1038/s41467-021-26783-x.

ABSTRACT

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

PMID:34785669 | PMC:PMC8595373 | DOI:10.1038/s41467-021-26783-x

BMJ Case Rep. 2021 Nov 16;14(11):e244298. doi: 10.1136/bcr-2021-244298.

ABSTRACT

Gaucher disease is an inborn error of metabolism resulting from the deficiency of the enzyme glucocerebrosidase and consequent accumulation of glucocerebroside within the lysosomes of macrophages. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease, and results from the progressive infiltration of lipid-laden cells in various organs. Common manifestations of Gaucher disease include enlarged liver and/or spleen (hepatosplenomegaly), bone marrow disease (pancytopenia) and bone abnormalities, which are extremely variable and can affect multiple skeletal sites. While bone involvement of long bones and vertebrae is a well-recognised feature of Gaucher disease, jawbone involvement is less commonly noted. Here, we describe a case of a 63-year-old patient with type 1 Gaucher disease with a history of long-term use of bisphosphonates and who had presented with dental pain, with subsequent investigations confirming the radiological features of jaw involvement in Gaucher disease, including periodontal disease.

PMID:34785512 | DOI:10.1136/bcr-2021-244298

Nat Rev Drug Discov. 2021 Dec;20(12):886-887. doi: 10.1038/d41573-021-00193-6.

NO ABSTRACT

PMID:34773079 | DOI:10.1038/d41573-021-00193-6

BMC Med Genomics. 2021 Nov 12;14(1):266. doi: 10.1186/s12920-021-01116-5.

ABSTRACT

BACKGROUND: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant morbidity and cost. Common variants in the calcium sensing receptor gene (CaSR) have been associated with NL. Rare inactivating CaSR variants classically cause hyperparathyroidism, hypercalcemia and hypocalciuria. However, NL and familial hypercalciuria have been paradoxically associated with select inactivating CaSR variants in three kindreds from Europe and Australia.

METHODS: To discover novel NL-associated CaSR variants from a geographically distinct cohort, 57 Pakistani families presenting with pediatric onset NL were recruited. The CaSR locus was analyzed by directed or exome sequencing.

RESULTS: We detected a heterozygous and likely pathogenic splice variant (GRCh37 Chr3:122000958A>G; GRCh38 Chr3:12228211A>G; NM_000388:c.1609-2A>G) in CaSR in one family with recurrent calcium oxalate stones. This variant would be predicted to cause exon skipping and premature termination (p.Val537Metfs*49). Moreover, a splice variant of unknown significance in an alternative CaSR transcript (GRCh37 Chr3:122000929G>C; GRCh38 Chr3:122282082G >C NM_000388:c.1609-31G >C NM_001178065:c.1609-1G >C) was identified in two additional families.

CONCLUSIONS: Sequencing of the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant, expanding the connection between the CaSR locus and nephrolithiasis.

PMID:34772415 | DOI:10.1186/s12920-021-01116-5

Cir Cir. 2021;89(S1):62-65. doi: 10.24875/CIRU.20001188.

ABSTRACT

Achenbach syndrome is a condition of unknown etiology, characterized by changes in the coloration of the skin of the fingers and associated with acute pain. There are few epidemiological data, but it is estimated that it is a rare condition, which exceptionally appears under 40 years of age. We present the case of a young woman who has been diagnosed with Achenbach syndrome thanks to her history and after ruling out rheumatic, vascular, and metabolic pathology. We finalize by discussing data on the pathology and the differences found with the case we describe here.

PMID:34762626 | DOI:10.24875/CIRU.20001188

Nat Commun. 2021 Nov 9;12(1):6306. doi: 10.1038/s41467-021-26674-1.

ABSTRACT

Rare genetic diseases are typically caused by a single gene defect. Despite this clear causal relationship between genotype and phenotype, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, we introduce a network approach for evaluating the impact of rare gene defects across biological scales. We construct a multiplex network consisting of over 20 million gene relationships that are organized into 46 network layers spanning six major biological scales between genotype and phenotype. A comprehensive analysis of 3,771 rare diseases reveals distinct phenotypic modules within individual layers. These modules can be exploited to mechanistically dissect the impact of gene defects and accurately predict rare disease gene candidates. Our results show that the disease module formalism can be applied to rare diseases and generalized beyond physical interaction networks. These findings open up new venues to apply network-based tools for cross-scale data integration.

PMID:34753928 | PMC:PMC8578255 | DOI:10.1038/s41467-021-26674-1

N Engl J Med. 2021 Nov 11;385(20):1868-1880. doi: 10.1056/NEJMoa2035790.

ABSTRACT

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.

METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.

RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.

CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

PMID:34758253 | DOI:10.1056/NEJMoa2035790

Pediatr Endocrinol Diabetes Metab. 2021;27(3):209-212. doi: 10.5114/pedm.2021.107714.

ABSTRACT

Familial hypercholesterolemia is a rare genetic disease, although it is amongst the commonest dyslipidemias. It characterized by raised cholesterol levels and normal triglyceride levels. Childhood presentation of familial hypercholesterolemia can cause early atherosclerotic plaque deposition in arteries and a markedly increased risk of coronary heart disease (CHD) at a young age. A thorough clinical examination, including identification of signs like cutaneous lesions and careful eye examination, can clinch the diagnosis.

PMID:34743504 | DOI:10.5114/pedm.2021.107714

Neurol Res Pract. 2021 Nov 8;3(1):56. doi: 10.1186/s42466-021-00156-7.

ABSTRACT

Rhombencephalitis is an orphan disease of multiple causes that may manifest with facial palsy, limb ataxia and reduced consciousness. Up to now it is described after COVID-19 infection and in this (personal) case was found up to 8 weeks after Comirnaty vaccination. So far, we do not fully understand the pathophysiological characteristics of encephalitis associated with SARS-CoV-2. In rare cases, vaccination may cause an immunological reaction and delayed inflammation, the consequences of which we have not yet deciphered. Rhombencephalitis should be considered as a rare potential mRNA-associated vaccination side effect.

PMID:34743758 | DOI:10.1186/s42466-021-00156-7

Eur J Med Genet. 2022 Jan;65(1):104370. doi: 10.1016/j.ejmg.2021.104370. Epub 2021 Nov 1.

ABSTRACT

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

PMID:34737116 | DOI:10.1016/j.ejmg.2021.104370

Orphanet J Rare Dis. 2021 Nov 4;16(1):470. doi: 10.1186/s13023-021-02100-z.

ABSTRACT

BACKGROUND: The Italian Clinical network for FSHD (ICNF) has established the Italian National Registry for FSHD (INRF), collecting data from patients affected by Facioscapulohumeral dystrophy (FSHD) and their relatives. The INRF has gathered data from molecular analysis, clinical evaluation, anamnestic information, and family history from more than 3500 participants.

METHODS: A data management framework, called Mediator Environment for Multiple Information Sources (MOMIS) FSHD Web Platform, has been developed to provide charts, maps and search tools customized for specific needs. Patients' samples and their clinical information derives from the Italian Clinical network for FSHD (ICNF), a consortium consisting of fourteen neuromuscular clinics distributed across Italy. The tools used to collect, integrate, and visualize clinical, molecular and natural history information about patients affected by FSHD and their relatives are described.

RESULTS: The INRF collected the molecular data regarding FSHD diagnosis conducted on 7197 subjects and identified 3362 individuals carrying a D4Z4 Reduced Allele (DRA): 1634 were unrelated index cases. In 1032 cases the molecular testing has been extended to 3747 relatives, 1728 carrying a DRA. Since 2009 molecular analysis has been accompanied by clinical evaluation based standardized evaluation protocols. In the period 2009-2020, 3577 clinical forms have been collected, 2059 follow the Comprehensive Clinical Evaluation form (CCEF). The integration of standardized clinical information and molecular data has made possible to demonstrate the wide phenotypic variability of FSHD. The MOMIS (Mediator Environment for Multiple Information Sources) data integration framework allowed performing genotype-phenotype correlation studies, and generated information of medical importance either for clinical practice or genetic counseling.

CONCLUSION: The platform implemented for the FSHD Registry data collection based on OpenClinica meets the requirement to integrate patient/disease information, as well as the need to adapt dynamically to security and privacy concerns. Our results indicate that the quality of data collection in a multi-integrated approach is fundamental for clinical and epidemiological research in a rare disease and may have great value in allowing us to redefine diagnostic criteria and disease markers for FSHD. By extending the use of the MOMIS data integration framework to other countries and the longitudinal systematic collection of standardized clinical data will facilitate the understanding of disease natural history and offer valuable inputs towards trial readiness. This approach is of high significance to FSHD medical community and also to rare disease research in general.

PMID:34736505 | PMC:PMC8567605 | DOI:10.1186/s13023-021-02100-z

Orphanet J Rare Dis. 2021 Nov 4;16(1):469. doi: 10.1186/s13023-021-02099-3.

ABSTRACT

BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late.

OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development.

PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening.

RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD.

CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

PMID:34736502 | PMC:PMC8567586 | DOI:10.1186/s13023-021-02099-3

Science. 2021 Nov 5;374(6568):672. doi: 10.1126/science.acx9539. Epub 2021 Nov 4.

ABSTRACT

[Figure: see text].

PMID:34735255 | DOI:10.1126/science.acx9539

Orphanet J Rare Dis. 2021 Nov 3;16(1):463. doi: 10.1186/s13023-021-02069-9.

ABSTRACT

BACKGROUND: Understanding the natural history of rare bone and mineral conditions is essential for improving clinical practice and the development of new diagnostics and therapeutics. Recruitment and long-term participation in registries are key challenges for researchers.

METHODS: To understand the user needs, the European Reference Network on Rare Bone Diseases (ERN BOND) and European Patient Advocacy Groups developed and implemented a multinational survey about the patient's preferred database content and functionality through an iterative consensus process. The survey was disseminated by national and international patient groups and healthcare professionals. The findings were analysed using descriptive statistics and multivariate regression.

RESULTS: There were 493 eligible responses from 378 adults, 15 children and 100 parents, guardians or carers (PGC) across 22 rare bone and mineral conditions. Osteogenesis imperfecta constituted 53.4% of responses. Contents related to improving treatment and medical services scored the highest and contents about anxiety and socializing scored less highly. Additional content was recommended by 205 respondents. Respondents preferred data entry by their Healthcare Provider (HCP). However, less than 50% of adults received followup from their specialist HCP at least annually and 29% were followed up as needed.

CONCLUSIONS: This survey of individuals, their family, guardians and carers has prioritised the key components for an EU-based rare bone and mineral condition research database. The survey highlights issues around collecting psychosocial impacts as well as measures of HCP trust. The survey demonstrated that using only specialist centre visits for data collection, while preferred by patients, will miss a substantial number of individuals, limiting generalisability. Combined HCP and patient platforms will be required to collect representative and complete natural history data for this patient group.

PMID:34732217 | PMC:PMC8564998 | DOI:10.1186/s13023-021-02069-9

Aktuelle Urol. 2021 Nov 3. doi: 10.1055/a-1645-0987. Online ahead of print.

ABSTRACT

Interstitial cystitis is a chronic orphan disease of the urinary bladder characterised by its main symptoms of bladder pain, persistent urge to void and urinary frequency. Due to a variety of confusable diseases and different pathophysiologies, the diagnosis of IC is still a diagnosis of exclusion and remains a challenge for doctors and patients alike. Patients often experience misdiagnosis and unsuccessful treatment for years. Therefore, the primary goal for these patients with chronic pain must be a rapid diagnosis and initiation of adequate treatment. This article focuses on transferring the consensus-based recommendations of the current German S2k guideline "Diagnosis and Treatment of Interstitial Cystitis" (IC/BPS) (2018 AWMF register No.: 043/050) into a practice-orientated and structured diagnostic work-up process.

PMID:34734396 | DOI:10.1055/a-1645-0987

Brain Commun. 2021 Sep 25;3(4):fcab221. doi: 10.1093/braincomms/fcab221. eCollection 2021.

ABSTRACT

Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in AP4B1, AP4M1, AP4E1 or AP4S1, which constitute the four subunits of this obligate complex. While the diagnosis of adaptor protein complex 4-associated hereditary spastic paraplegia relies on molecular testing, the interpretation of novel missense variants remains challenging. Here, we address this diagnostic gap by using patient-derived fibroblasts to establish a functional assay that measures the subcellular localization of ATG9A, a transmembrane protein that is sorted by adaptor protein complex 4. Using automated high-throughput microscopy, we determine the ratio of the ATG9A fluorescence in the trans-Golgi-network versus cytoplasm and ascertain that this metric meets standards for screening assays (Z'-factor robust >0.3, strictly standardized mean difference >3). The 'ATG9A ratio' is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 ± 0.13 versus 1.21 ± 0.05 (standard deviation) in controls] and receiver-operating characteristic analysis demonstrates robust diagnostic power (area under the curve: 0.85, 95% confidence interval: 0.849-0.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in AP4B1, we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the 'ATG9A ratio' as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.

PMID:34729478 | PMC:PMC8557665 | DOI:10.1093/braincomms/fcab221

Rev Esp Salud Publica. 2021 Nov 2;95:e202111186.

ABSTRACT

Traditionally, epidemiological surveillance has focused on infectious diseases, but the concept of Public Health surveillance, introduced in Spain with the Law 33/2011, is broader and includes chronic diseases. Health strategies for these diseases need epidemiological information to improve understanding of socio-health needs and to facilitate the efficient management of resources. The European Union defines rare diseases (RD) as those that, being life-threatening or chronically debilitating, have a prevalence of less than 5 cases per 10,000 inhabitants. The RD Strategy of the National Health System, approved in 2009 and updated in 2014, recommends the development of regional registries of rare diseases (RAER), in addition to a national registry. The REpIER and Spain-RDR projects of the Institute of Health Carlos III (ISCIII) promoted the creation and regulation of 94% of the RAER. After more than 10 years of initiatives and work to improve the knowledge of RD's epidemiology in Spain, it was possible to implement the Spanish Registry of Rare Diseases (ReeR) in 2015, becoming one of the first population surveillance systems for chronic diseases of state scope. The ReeR procedures manual is the result of consensus between the RAER, the Ministry of Health, the ISCIII and the patient associations. The participatory methodology used for the implementation and launching of ReeR is considered an added value. The information system implemented will allow improving knowledge about the prevalence and distribution of RD in Spain.

PMID:34725319

Cancer Discov. 2021 Nov;11(11):2674-2676. doi: 10.1158/2159-8290.CD-21-1046.

ABSTRACT

Chimeric antigen receptor (CAR) T cells targeting mesothelin plus pembrolizumab, and atezolizumab plus bevacizumab, have recently shown clinical efficacy in phase I trials in malignant pleural and peritoneal mesothelioma. Despite being tested in a highly selected patient population and requiring a complex engineering that can hardly be upscaled, CAR T cells combined with pembrolizumab bring the first proof of efficacy in cold solid tumors with low genomic heterogeneity, while atezolizumab-bevacizumab offers an easy-to-use combination of antiangiogenics and immunotherapy in an orphan disease.See related article by Raghav et al., p. 2738.See related article by Adusumilli et al., p. 2748.

PMID:34725087 | DOI:10.1158/2159-8290.CD-21-1046

Case Rep Oncol. 2021 Sep 21;14(3):1359-1365. doi: 10.1159/000518079. eCollection 2021 Sep-Dec.

ABSTRACT

TAFRO syndrome is defined by the presence of thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis/renal dysfunction (R), and organomegaly (O) and can be seen with idiopathic multicentric Castleman disease (iMCD) or as an isolated process without iMCD. Although the diagnosis of iMCD in patients with TAFRO can be challenging to make, iMCD should remain high on the differential diagnosis. Similar to iMCD, the pathophysiology of TAFRO is not well understood but is thought to be related to hypercytokinemia, with interleukin (IL)-6 playing a pivotal role. Anti-IL-6 monoclonal antibody therapy is an effective treatment modality for iMCD, but to date, there is no clear guidance on treatment of TAFRO in the absence of definitive diagnosis of iMCD, leading to suboptimal management and high morbidity. We report a case of TAFRO syndrome and demonstrate benefit with the empiric use of anti-IL-6 antibody therapy in the context of delayed diagnosis of iMCD.

PMID:34720942 | PMC:PMC8525304 | DOI:10.1159/000518079