hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to ...life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, ...implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and ...software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
As a multisystem disorder, Andersen–Tawil syndrome (ATS) is rather unique in the family of channelopathies. The full spectrum of the disease is characterized by ventricular arrhythmias, dysmorphic ...features, and periodic paralysis. Most ATS patients have a mutation in the ion channel gene,
KCNJ2
, which encodes the inward rectifier K
+
channel Kir2.1, a component of the inward rectifier
I
K1
.
I
K1
provides repolarizing current during the most terminal phase of repolarization and is the primary conductance controlling the diastolic membrane potential. Thus, ATS is a disorder of cardiac repolarization. The chapter will discuss the most recent data concerning the genetic, cellular, and clinical data underlying this unique disorder.
Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations ...in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over 150,000 yearly strokes in the United States occur in patients with AF.1 Many of these occur in patients with AF who are misclassified as low-risk or fail to receive appropriate therapies because ...of healthcare disparities. ...there remains a critical need for personalized, socially aware, and equitable stroke risk prediction for patients with AF. In Figure 1, risk factors such as diabetes mellitus and hypertension do not yield similar risks of stroke (1.32 × and 1.92 ×, respectively), though they are accorded the same value when determining CHADS2-VA2Sc score (1 point each). ...in patients with a CHADS2-VA2Sc score in the treatment “Twilight” zone (∼2), there is wide variability in relative risk (1.32 × to 2.26 ×). ...patients of American Indian or Pacific Islander ancestry with Medicaid have a greater than 50% increased risk of stroke compared with Hispanic patients with Medicaid. ...there exist subgroups of patients for whom certain SDoH factors are critical for accurate risk stratification.
Background
Pathogenic variants in the L‐type Ca2+ channel gene CACNA1C cause a multi‐system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial ...features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac‐only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra‐cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations.
Methods
A four‐generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great‐uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant.
Results
In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome.
Conclusion
Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L‐type Ca2+ channel.
We present a four‐generation family harboring the CACNA1C p.R518C pathogenic variant that, in addition to displaying cardinal features of CACNA1C disorders including Long QT syndrome, congenital heart disease, hypertrophic cardiomyopathy, and sudden cardiac death, also manifest atrial fibrillation and sick sinus syndrome. Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L‐type calcium channel.
The Long and Short of It Tristani-Firouzi, Martin, MD
Journal of the American College of Cardiology,
04/2014, Letnik:
63, Številka:
13
Journal Article
Recenzirano
By perturbing the gating properties that limit potassium ion efflux during the plateau phase, cardiac repolarization is accelerated, resulting in shortening of atrial and ventricular action potential ...duration, arrhythmia susceptibility, and sudden death. Because IK1, IKr, and IKs each contribute differentially to cardiac repolarization, gene-specific mutations will differentially influence repolarization and the susceptibility to arrhythmia. ...the combination of reduced affinity of mutant KCNH2 channel and the relatively low potency might explain the ineffectiveness of d-sotalol to prolong the QT interval in these patients.
Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS ...identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome‐wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools.
Here, we introduce the Mendelian Error Method (MEM), a novel tool to identify deletion CNVs based on the clustering of Mendelian errors (MEs) in whole exome and genome sequencing data from of trios. We show MEM deletion calls achieve validation rates of 88–97%, and can identify additional de novo deletions that are missed by read‐depth based methods such as XHMM. In addition, MEM is able to robustly identify cases of uniparental disomy, sample switches, and DNA contamination.
The American Heart Association's Strategically Focused Children's Research Network started in July 2017 with 4 unique programs at Children's National Hospital in Washington, DC; Duke University in ...Durham, North Carolina; University of Utah in Salt Lake City, Utah; and Lurie Children's Hospital/Northwestern University in Chicago, Illinois. The overarching goal of the Children's National center was to develop evidence-based strategies to strengthen the health system response to rheumatic heart disease through synergistic basic, clinical, and population science research. The overall goals of the Duke center were to determine risk factors for obesity and response to treatment including those that might work on a larger scale in communities across the country. The integrating theme of the Utah center focused on leveraging big data-science approaches to improve the quality of care and outcomes for children with congenital heart defects, within the context of the patient and their family. The overarching hypothesis of the Northwestern center is that the early course of change in cardiovascular health, from birth onward, reflects factors that result in either subsequent development of cardiovascular risk or preservation of lifetime favorable cardiovascular health. All 4 centers exceeded the original goals of research productivity, fellow training, and collaboration. This article describes details of these accomplishments and highlights challenges, especially around the COVID-19 pandemic.
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