A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network.
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ABSTRACT:
SUBMITTER: Reuter CM
PROVIDER: S-EPMC5924635 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network.
Reuter Chloe M CM Brimble Elise E DeFilippo Colette C Dries Annika M AM Enns Gregory M GM Ashley Euan A EA Bernstein Jonathan A JA Fisher Paul Graham PG Wheeler Matthew T MT
The Journal of pediatrics 20180111
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Project description:ObjectiveWhen studying any specific rare disease, heterogeneity and scarcity of affected individuals has historically hindered investigators from discerning on what to focus to understand and diagnose a disease. New nongenomic methodologies must be developed that identify similarities in seemingly dissimilar conditions.Materials and methodsThis observational study analyzes 1042 patients from the Undiagnosed Diseases Network (2015-2019), a multicenter, nationwide research study using phenotypic data annotated by specialized staff using Human Phenotype Ontology terms. We used Louvain community detection to cluster patients linked by Jaccard pairwise similarity and 2 support vector classifier to assign new cases. We further validated the clusters' most representative comorbidities using a national claims database (67 million patients).ResultsPatients were divided into 2 groups: those with symptom onset before 18 years of age (n = 810) and at 18 years of age or older (n = 232) (average symptom onset age: 10 [interquartile range, 0-14] years). For 810 pediatric patients, we identified 4 statistically significant clusters. Two clusters were characterized by growth disorders, and developmental delay enriched for hypotonia presented a higher likelihood of diagnosis. Support vector classifier showed 0.89 balanced accuracy (0.83 for Human Phenotype Ontology terms only) on test data.DiscussionsTo set the framework for future discovery, we chose as our endpoint the successful grouping of patients by phenotypic similarity and provide a classification tool to assign new patients to those clusters.ConclusionThis study shows that despite the scarcity and heterogeneity of patients, we can still find commonalities that can potentially be harnessed to uncover new insights and targets for therapy.
| S-EPMC8324228 | biostudies-literature
Project description:BackgroundFor a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many "Undiagnosed RDs programs" have been gradually developed on the grounds of a well-structured multidisciplinary approach.MethodsThe Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases.ResultsOne hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement.ConclusionsOur results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.
| S-EPMC7488856 | biostudies-literature
Project description:One of the IRDiRC goals for 2017⁻2027 is to achieve definitive diagnosis for rare undiagnosed diseases within one year, as delay in diagnosis remains one of the pending issues in the rare diseases field. The Spanish Undiagnosed Rare Diseases Program (SpainUDP) was created in response to this challenging scenario to cover patients' needs and after seeing the success of the Undiagnosed Diseases Program (UDP) in the USA. SpainUDP offers a multidisciplinary approach to those patients who have long sought a diagnosis without any success. During the first phase of the protocol, undiagnosed cases are sent to SpainUDP by individual patients or families, patient organizations or hospitals. After careful analysis of phenotype, data from sequencing experiments (WES) is processed with a standard pipeline and detailed standardized phenotypic information (mapped to the Human Phenotype Ontology, HPO) is connected to genetic data. In addition, the participation of SpainUDP in international initiatives such as the European projects RD-Connect and Solve RD, the Undiagnosed Diseases Network International (UDNI), and the MatchMaker Exchange (MME) platform, allows the establishment of a global data sharing strategy across multiple projects submitting data to these international initiatives. From the official beginning of the program (at the end of 2015) until early 2018, 147 cases were accepted in SpainUDP. During this time, 37 cases (25%) dropped out the program due to several reasons. The remaining 110 cases are distributed as follows: phenotypic and genotypic (WES) characterization was finished in 30 cases, of which 20 (67%) were diagnosed; 21 cases are pending on variants' validation by Sanger sequencing; in 25 cases, WES is ongoing and 34 cases are being studied for deep phenotypic characterization. In conclusion, SpainUDP aims to achieve a diagnosis following two recommendations of the IRDiRC: the patients' diagnosis in as short a time as possible and the promotion of data sharing (especially genomic) at the international level.
| S-EPMC6121381 | biostudies-literature
Project description:PURPOSE:This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. METHODS:Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. RESULTS:Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. CONCLUSION:The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.
| S-EPMC4098846 | biostudies-literature
Project description:Undiagnosed and rare conditions are collectively common and affect millions of people worldwide. The NIH Undiagnosed Diseases Program (UDP) strives to achieve both a comprehensive diagnosis and a better understanding of the mechanisms of disease for many of these individuals. Through the careful review of records, a well-orchestrated inpatient evaluation, genomic sequencing and testing, and with the use of emerging strategies such as matchmaking programs, the UDP succeeds nearly 30 percent of the time for these highly selective cases. Although the UDP process is built on a unique set of resources, case examples demonstrate steps genetic professionals can take, in both clinical and research settings, to arrive at a diagnosis for their most challenging cases.
| S-EPMC7250153 | biostudies-literature
Project description:PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
| S-EPMC5851806 | biostudies-literature
Project description:ObjectivesTo review the referral and clinical characteristics of adult patients diagnosed with lysosomal storage diseases (LSD) through the Undiagnosed Diseases Network (UDN).MethodsRetrospective review of both application and evaluation records for adults admitted to the UDN with a final diagnosis of a lysosomal storage disease.ResultsTen patients were identified. Final diagnoses included late onset Tay Sachs, attenuated MPS I, MPS IIIA, MPS IIIB, and MPS IIIC. Most patients presented with neurocognitive changes. Prior to referral, all patients had been evaluated by neurology, four patients underwent phenotype specific panel testing that did not include the causative gene, and four patients had non-diagnostic clinical exome sequencing.ConclusionsLSDs figure highly in the differential diagnosis of neurometabolic disorders in pediatric onset progressive diseases. In adults, their subtle initial presentations overlap with symptoms of more common disorders and less practitioner awareness may lead to prolonged diagnostic challenges.
| S-EPMC9482386 | biostudies-literature
Project description:While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.
| S-EPMC8057342 | biostudies-literature
Project description:BackgroundAlthough clinician, researcher, and patient resources for matchmaking exist, finding similar patients remains an obstacle for rare disease diagnosis. The goals of this study were to develop and test the effectiveness of an Internet case-finding strategy and identify factors associated with increased matching within a rare disease population.MethodsPublic web pages were created for consented participants. Matches made, time to each inquiry and match, and outcomes were recorded and analyzed using descriptive statistics. A Poisson regression model was run to identify characteristics associated with matches.Results385 participants were referred to the project and 158 had pages posted. 579 inquiries were received; 89.0% were from the general public and 24.7% resulted in a match. 81.6% of pages received at least one inquiry and 15.0% had at least one patient match. Primary symptom category of neurology, diagnosis, gene page, and photo were associated with increased matches (p ≤ 0.05).ConclusionsThis Internet case-finding strategy was of interest to patients, families, and clinicians, and similar patients were identified using this approach. Extending matchmaking efforts to the general public resulted in matches and suggests including this population in matchmaking activities can improve identification of similar patients.
| S-EPMC8108446 | biostudies-literature
Project description:The global burden of undiagnosed diseases, particularly in adults, is rising due to their significant socioeconomic impact. To address this, we enrolled 232 adult probands with undiagnosed conditions, utilizing bioinformatics tools for genetic analysis. Alongside exome and genome sequencing, repeat-primed PCR and Cas9-mediated nanopore sequencing were applied to suspected short tandem repeat disorders. Probands were classified into probable genetic (n = 128) or uncertain (n = 104) origins. The study found genetic causes in 66 individuals (28.4%) and non-genetic causes in 12 (5.2%), with a longer diagnostic journey for those in the probable genetic group or with pediatric symptom onset, emphasizing the need for increased efforts in these populations. Genetic diagnoses facilitated effective surveillance, cascade screening, drug repurposing, and pregnancy planning. This study demonstrates that integrating sequencing technologies improves diagnostic accuracy, may shorten the time to diagnosis, and enhances personalized management for adults with undiagnosed diseases.
| S-EPMC11604660 | biostudies-literature