Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the ...read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch .
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as ...the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.
BACKGROUNDWest Nile virus (WNV), a global arbovirus, is the most prevalent mosquito-transmitted infection in the United States. Forecasts of WNV risk during the upcoming transmission season could ...provide the basis for targeted mosquito control and disease prevention efforts. We developed the Arbovirus Mapping and Prediction (ArboMAP) WNV forecasting system and used it in South Dakota from 2016 to 2019. This study reports a post hoc forecast validation and model comparison. OBJECTIVESOur objective was to validate historical predictions of WNV cases with independent data that were not used for model calibration. We tested the hypothesis that predictive models based on mosquito surveillance data combined with meteorological variables were more accurate than models based on mosquito or meteorological data alone. METHODSThe ArboMAP system incorporated models that predicted the weekly probability of observing one or more human WNV cases in each county. We compared alternative models with different predictors including a) a baseline model based only on historical WNV cases, b) mosquito models based on seasonal patterns of infection rates, c) environmental models based on lagged meteorological variables, including temperature and vapor pressure deficit, d) combined models with mosquito infection rates and lagged meteorological variables, and e) ensembles of two or more combined models. During the WNV season, models were calibrated using data from previous years and weekly predictions were made using data from the current year. Forecasts were compared with observed cases to calculate the area under the receiver operating characteristic curve (AUC) and other metrics of spatial and temporal prediction error. RESULTSMosquito and environmental models outperformed the baseline model that included county-level averages and seasonal trends of WNV cases. Combined models were more accurate than models based only on meteorological or mosquito infection variables. The most accurate model was a simple ensemble mean of the two best combined models. Forecast accuracy increased rapidly from early June through early July and was stable thereafter, with a maximum AUC of 0.85. The model predictions captured the seasonal pattern of WNV as well as year-to-year variation in case numbers and the geographic pattern of cases. DISCUSSIONThe predictions reached maximum accuracy early enough in the WNV season to allow public health responses before the peak of human cases in August. This early warning is necessary because other indicators of WNV risk, including early reports of human cases and mosquito abundance, are poor predictors of case numbers later in the season. https://doi.org/10.1289/EHP10287.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide ...sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.
We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required.
Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with
and
. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations
.
Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.
Abstract
Background
Key indicators of vulnerability for the syndemic of opioid overdose, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) due to injection drug use (IDU) in rural ...reservation and frontier counties are unknown. We examined county-level vulnerability for this syndemic in South Dakota.
Methods
Informed by prior methodology from the Centers for Disease Control and Prevention, we used acute and chronic HCV infections among persons aged ≤40 years as a proxy measure of IDU. Twenty-nine county-level indicators potentially associated with HCV infection rates were identified. Using these indicators, we examined relationships through bivariate and multivariate analysis and calculated a composite index score to identify the most vulnerable counties (top 20%) to this syndemic.
Results
Of the most vulnerable counties, 69% are reservation counties and 62% are rural. The county-level HCV infection rate is 4 times higher in minority counties than nonminority counties, and almost all significant indicators of opioid-related vulnerability in our analysis are structural and potentially modifiable through public health interventions and policies.
Conclusions
Our assessment gives context to the magnitude of this syndemic in rural reservation and frontier counties and should inform the strategic allocation of prevention and intervention services.
•Lethal arthrogryposis and pterygia resulting from bi-allelic MYH3 variants.•Expanding phenotype of MYH3-disease.•Minigene assays clarified splicing defects.
Arthrogryposis is a consequence of ...reduced fetal movements and arises due to environmental factors or underlying genetic defects, with extensive genetic heterogeneity. In many instances, the genes responsible are involved in neuromuscular function. Missense variants in the gene encoding embryonic myosin heavy chain (MYH3) usually cause distal arthrogryposis. Recently, mono-allelic or bi-allelic MYH3 variants have been associated with contractures, pterygia, and spondylocarpotarsal fusion syndrome 1 (CPSFS1A and CPSFS1B). Here we describe three fetuses presenting in the second trimester with a lethal form of arthrogryposis and pterygia and harbouring bi-allelic variants in MYH3. One proband was compound heterozygous for a missense change and an extended splice site variant, a second proband had a homozygous frameshift variant, and a third proband was homozygous for a nonsense variant. Minigene assays performed on the first fetus showed that the missense and extended splice site variants resulted in aberrant splicing, likely resulting in near complete loss of full-length MYH3 transcript. This study shows that loss of MYH3 is associated with a lethal arthrogryposis phenotype and highlights the utility of minigene assays to assess splicing.
Detailed biogeographic studies of pantropical clades are still relatively few, and those conducted to date typically use parsimony or event-based methods to reconstruct ancestral areas. In this ...study, a recently developed likelihood method for reconstructing ancestral areas (the dispersal–extinction cladogenesis DEC model) is applied to the angiosperm family Simaroubaceae, a geographically widespread and ecologically diverse clade of pantropical and temperate trees and shrubs. To estimate divergence dates in the family, Bayesian uncorrelated rates analyses and robust fossil calibrations are applied to the well-sampled and strongly supported phylogeny. For biogeographic analyses, the effects of parameter configurations in the DEC model are assessed for different possible ancestral ranges, and the likelihood method is compared with dispersal–vicariance analysis (DIVA). Regardless of the parameters used, likelihood analyses show a common pattern of multiple recent range shifts that overshadow reconstruction of events deeper in the family's history. DIVA produced results similar to the DEC model when ancestral ranges were restricted to two areas, but some improbable ancestral ranges were also observed. Simaroubaceae exhibit an early history of range expansion between major continental areas in the Northern Hemisphere, but reconstruction of ancestral areas for lineages diverging in the early Tertiary are sensitive to the parameters of the model used. A North American origin is suggested for the family, with migration via Beringia by ancestral taxa. In contrast to traditional views, long-distance dispersal events are common, particularly in the Late Oligocene and later. Notable dispersals are inferred to have occurred across the Atlantic Ocean in both directions, as well as between Africa and Asia, and around the Indian Ocean basin and Pacific islands.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we generated iPSC lines from two ...patients with CCD and MH caused by dominant RYR1 variants within the central region of the protein (p.Val2168Met and p.Arg2508Cys). Both lines displayed typical iPSC morphology, uniform expression of pluripotency markers, trilineage differentiation potential, and had normal karyotypes. These are the first RYR1 iPSC lines from patients with both CCD and MH. As these are common CCD/MH variants, these lines should be useful to study these conditions and test therapeutics.
RYR1 variants are a common cause of congenital myopathies, including multi-minicore disease (MmD) and central core disease (CCD). Here, we generated iPSC lines from two CCD patients with dominant ...RYR1 missense variants that affect the transmembrane (pore) and SPRY3 protein domains (p.His4813Tyr and p.Asn1346Lys, respectively). Both lines had typical iPSC morphology, expressed canonical pluripotency markers, exhibited trilineage differentiation potential, and had normal karyotypes. Together with existing RYR1 iPSC lines, these represent important tools to study and develop treatments for RYR1-related myopathies.
We used gene editing to introduce DNA sequences encoding the tdTomato fluorescent protein into the α -skeletal actin 1 (ACTA1) locus to develop an ACTA1-tdTomato induced pluripotent stem cell ...reporter line for monitoring differentiation of skeletal muscle. This cell line will be used to better understand skeletal muscle maturation and development in vitro as well as provide a useful tool for drug screening and the evaluation of novel therapeutics for the treatment of skeletal muscle disease.
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