Application of full-genome analysis to diagnose rare monogenic disorders.
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ABSTRACT:
SUBMITTER: Shieh JT
PROVIDER: S-EPMC8460793 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC10671883 | biostudies-literature
Project description:BackgroundRecently an increasing number of digital tools to aid clinical work have been published. This study's aim was to create an algorithm which can assist physicians as a "digital expert" with the differential diagnosis of central ocular motor disorders, in particular in rare diseases.ResultsThe algorithm's input consists of a maximum of 60 neurological and oculomotor signs and symptoms. The output is a list of the most probable diagnoses out of 14 alternatives and the most likely topographical anatomical localizations out of eight alternatives. Positive points are given for disease-associated symptoms, negative points for symptoms unlikely to occur with a disease. The accuracy of the algorithm was evaluated using the two diagnoses and two brain zones with the highest scores. In a first step, a dataset of 102 patients (56 males, 48.0 ± 22 yrs) with various central ocular motor disorders and underlying diseases, with a particular focus on rare diseases, was used as the basis for developing the algorithm iteratively. In a second step, the algorithm was validated with a dataset of 104 patients (59 males, 46.0 ± 23 yrs). For 12/14 diseases, the algorithm showed a sensitivity of between 80 and 100% and the specificity of 9/14 diseases was between 82 and 95% (e.g., 100% sensitivity and 75.5% specificity for Niemann Pick type C, and 80% specificity and 91.5% sensitivity for Gaucher's disease). In terms of a topographic anatomical diagnosis, the sensitivity was between 77 and 100% for 4/8 brain zones, and the specificity of 5/8 zones ranged between 79 and 99%.ConclusionThis algorithm using our knowledge of the functional anatomy of the ocular motor system and possible underlying diseases is a useful tool, in particular for the diagnosis of rare diseases associated with typical central ocular motor disorders, which are often overlooked.
| S-EPMC6688379 | biostudies-literature
Project description:Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.
| S-EPMC7952289 | biostudies-literature
Project description:ObjectivesWhole exome sequencing (WES) has been widely used to detect genetic disorders in critically ill children. Relevant data are lacking in pediatric intensive care units (PICUs) of China. This study aimed to investigate the spectrum of monogenic disorders, the diagnostic yield and clinical utility of WES from a PICU in a large children's hospital of China.MethodsFrom July 2017 to February 2020, WES was performed in 169 critically ill children with suspected monogenic diseases in the PICU of Beijing Children's Hospital. The clinical features, human phenotype ontology (HPO) terms, and assessment of clinical impact were analyzed.ResultsThe media age of the enrolled children was 10.5 months (range, 1 month to 14.8 years). After WES, a total of 43 patients (25%) were diagnosed with monogenic disorders. The most common categories of diseases were metabolic disease (33%), neuromuscular disease (19%), and multiple deformities (14%). The diagnosis yield of children with "metabolism/homeostasis disorder" and "growth delay" or "ocular anomalies" was higher than that of children without these features. In addition, the diagnosis rate increased when more features were observed in children. The results of WES had an impact on the treatment for 30 cases (70%): (1) change of treatment (n = 11), (2) disease monitoring initiation (n = 18), (3) other systemic evaluation (n = 3), (4) family intervention (n = 2), and (5) rehabilitation and redirection of care toward palliative care (n = 12).ConclusionWES can be used as an effective diagnostic tool in the PICU of China and has an important impact on the treatment of patients with suspected monogenic conditions.
| S-EPMC8440967 | biostudies-literature
Project description:Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.
| S-EPMC6067656 | biostudies-literature
Project description:PURPOSE OF REVIEW:Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions. RECENT FINDINGS:Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,. Thanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.
| S-EPMC5662693 | biostudies-literature
Project description:The practice of genomic medicine stands to revolutionize our approach to medical care, and to realize this goal will require discovery of the relationship between rare variation at each of the ~ 20,000 protein-coding genes and their consequent impact on individual health and expression of Mendelian disease. The step-wise evolution of broad-based, genome-wide cytogenetic and molecular genomic testing approaches (karyotyping, chromosomal microarray [CMA], exome sequencing [ES]) has driven much of the rare disease discovery to this point, with genome sequencing representing the newest member of this team. Each step has brought increased sensitivity to interrogate individual genomic variation in an unbiased method that does not require clinical prediction of the locus or loci involved. Notably, each step has also brought unique limitations in variant detection, for example, the low sensitivity of ES for detection of triploidy, and of CMA for detection of copy neutral structural variants. The utility of genome sequencing (GS) as a clinical molecular diagnostic test, and the increased sensitivity afforded by addition of long-read sequencing or other -omics technologies such as RNAseq or metabolomics, are not yet fully explored, though recent work supports improved sensitivity of variant detection, at least in a subset of cases. The utility of GS will also rely upon further elucidation of the complexities of genetic and allelic heterogeneity, multilocus rare variation, and the impact of rare and common variation at a locus, as well as advances in functional annotation of identified variants. Much discovery remains to be done before the potential utility of GS is fully appreciated.
| S-EPMC6591893 | biostudies-literature
Project description:Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform "N-of-1" analyses on individual patients. The increasing sizes of ultra-rare, "N-of-1" disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development.1,2 The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We apply existing and introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We make our gene-level findings and variant-level information across the cohort available in a public-facing browser (https://dbmi-bgm.github.io/udn-browser/). These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts.
| S-EPMC10888768 | biostudies-literature
Project description:Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.
| S-EPMC10432178 | biostudies-literature
Project description:BackgroundMonogenic diseases are individually rare but collectively common, and are likely underdiagnosed.ObjectivesThe purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort.MethodsExomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease.ResultsIn total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals.ConclusionsOverall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.
| S-EPMC7428466 | biostudies-literature