OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

• MeSH
• dítě MeSH
• elektroencefalografie * metody   MeSH
• epilepsie MeSH
• fokální kortikální dysplazie MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• malformace mozkové kůry, skupina I * chirurgie   komplikace   diagnostické zobrazování   MeSH
• malformace mozkové kůry chirurgie   komplikace   diagnostické zobrazování   MeSH
• mladiství MeSH
• pozitronová emisní tomografie MeSH
• předškolní dítě MeSH
• refrakterní epilepsie * chirurgie   diagnostické zobrazování   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• časopisecké články MeSH

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

• MeSH
• databáze genetické MeSH
• exom genetika   MeSH
• genom lidský genetika   MeSH
• genomika * metody   MeSH
• lidé MeSH
• rodokmen MeSH
• výpočetní biologie metody   MeSH
• vzácné nemoci * genetika   diagnóza   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

• MeSH
• Bayesova věta MeSH
• kardiopulmonální resuscitace * MeSH
• lidé MeSH
• srdeční zástava * terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

• MeSH
• enzymy opravy DNA genetika   MeSH
• genové regulační sítě MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• missense mutace MeSH
• neurovývojové poruchy * genetika   MeSH
• sestřih RNA MeSH
• sestřihové faktory genetika   MeSH
• spliceozomy * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Guidelines recommend case finding for dysglycemia (prediabetes and type 2 diabetes [T2D]) in adults or youth older than 10 years with overweight/obesity, but increased adiposity has not been associated with dysglycemia in some Hispanic populations. This study aims to determine the prevalence of dysglycemia in this population using simplified criteria independent of body mass index and age to request an oral glucose tolerance test (OGTT). METHODS: Cross-sectional retrospective analysis of medical records from a clinical center in Chile (2000-2007). OGTT was obtained from any patient with 1 cardiometabolic risk factor (CMRF) independent of age and body mass index. RESULTS: In total, 4969 adults (mean age ± SD) 45.7 ± 15.9 years and 509 youths 16.6 ± 3.0 years were included. The prevalence (%, 95% CI) of prediabetes doubled that of T2D in youths (14.1%, 1.4-17.4 vs 6.3%, 4.5-8.7) and tripled it in adults (36.0%, 34.7-37.4 vs 10.7%, 9.8-11.5). In underweight and normal-weight adults, 22% (12.0-36.7) and 29.2% (26.4-32.1) had prediabetes, whereas 4.9% (1.3-16.1) and 8.8% (7.2-10.7) had T2D, respectively. In normal weight youths, 10.5% (6.7-15.9) and 2.9% (1.2-6.6) had prediabetes and T2D, respectively. In adults, but not in youths, most dysglycemia categories were related to overweight/obesity. CONCLUSION: This study supports a public health policy to identify more people at risk for cardiovascular disease by implementing a revised case finding protocol for dysglycemia using OGTT in even normal weight patients over 6 years of age when there is at least 1 CMRF. Reanalysis of case finding protocols for cardiometabolic risk in other populations is warranted.

• MeSH
• diabetes mellitus 2. typu * komplikace   MeSH
• dospělí MeSH
• krevní glukóza MeSH
• lidé MeSH
• mladiství MeSH
• nadváha epidemiologie   MeSH
• obezita epidemiologie   komplikace   MeSH
• prediabetes * epidemiologie   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Chile MeSH

Small erythrocytes might be beneficial for blood rheology, as they contribute less to blood viscosity than large erythrocytes. We predicted that rheological disadvantages of larger erythrocytes could be alleviated by relatively smaller nucleus size in larger cells allowing higher flexibility and by more elongated shape. Across squamate reptiles, we found that species with larger erythrocytes tend to have smaller ratio of nucleus size to cell size (N : C ratio), but that larger erythrocytes tend to be rounder, not more elongated. Nevertheless, we document that in fact nucleus area changes with erythrocyte area more or less linearly, which is also true for the relationship between cell length and cell width. These linear relationships suggest that nucleus size and cell size, and cell width and cell length, might be constrained to largely proportional mutual changes. The shifts in widely used N : C ratio and elongation ratio (cell length/cell width) with cell size might be misleading, as they do not reflect adaptive or maladaptive changes of erythrocytes, but rather mathematically trivial scaling of the ratios of two variables with a linear relationship with non-zero intercepts. We warn that ratio scaling without analyses of underlying patterns of evolutionary changes can lead to misinterpretation of evolutionary processes.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: The benefit of the ICU for older patients is often debated. There is little knowledge on subjective impressions of excessive care in ICU nurses and physicians combined with objective patient data in real-life cases. RESEARCH QUESTION: Is there a difference in treatment limitation decisions and 1-year outcomes in patients < 75 and ≥ 75 years of age, with and without concordant perceptions of excessive care by two or more ICU nurses and physicians? STUDY DESIGN AND METHODS: This was a reanalysis of the prospective observational DISPROPRICUS study, performed in 56 ICUs. Nurses and physicians completed a daily questionnaire about the appropriateness of care for each of their patients during a 28-day period in 2014. We compared the cumulative incidence of patients with concordant perceptions of excessive care, treatment limitation decisions, and the proportion of patients attaining the combined end point (death, poor quality of life, or not being at home) at 1 year across age groups via Cox regression with propensity score weighting and Fisher exact tests. RESULTS: Of 1,641 patients, 405 (25%) were ≥ 75 years of age. The cumulative incidence of concordant perceptions of excessive care was higher in older patients (13.6% vs 8.5%; P < .001). In patients with concordant perceptions of excessive care, we found no difference between age groups in risk of death (1-year mortality, 83% in both groups; P > .99; hazard ratio [HR] after weighting, 1.11; 95% CI, 0.74-1.65), treatment limitation decisions (33% vs 31%; HR after weighting, 1.11; 95% CI, 0.69-2.17), and reaching the combined end point at 1 year (90% vs 93%; P = .546). In patients without concordant perceptions of excessive care, we found a difference in risk of death (1-year mortality, 41% vs 30%; P < .001; HR after weighting, 1.38; 95% CI, 1.11-1.73) and treatment limitation decisions (11% vs 5%; P < .001; HR, 2.11; 95% CI, 1.37-3.27); however, treatment limitation decisions were mostly documented prior to ICU admission. The risk of reaching the combined end point was higher in the older adults (61.6% vs 52.8%; P < .001). INTERPRETATION: Although the incidence of perceptions of excessive care is slightly higher in older patients, there is no difference in treatment limitation decisions and 1-year outcomes between older and younger patients once patients are identified by concordant perceptions of excessive care. Additionally, in patients without concordant perceptions, the outcomes are worse in the older adults, pleading against ageism in ICU nurses and physicians.

• MeSH
• hospitalizace MeSH
• jednotky intenzivní péče MeSH
• kvalita života MeSH
• lékaři * MeSH
• lidé MeSH
• senioři MeSH
• zdravotní sestry * MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

PURPOSE: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. METHODS: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. RESULTS: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). CONCLUSION: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

• MeSH
• alely MeSH
• genotyp MeSH
• lidé MeSH
• mentální retardace * diagnóza   genetika   MeSH
• sekvenování exomu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

• MeSH
• celogenomová asociační studie MeSH
• DNA MeSH
• duktální karcinom slinivky břišní * genetika   MeSH
• genetická predispozice k nemoci MeSH
• genom lidský MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH