Atlas of the clinical genetics of human dilated cardiomyopathy

AIM: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSIONS: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM

Arrhythmias in Dilated Cardiomyopathy: Diagnosis and Treatment

In patients with dilated cardiomyopathy (DCM), it is possible to find a broad range of bradyrhythmias and tachyarrhythmias. Bradyrhythmias and supraventricular arrhythmias can frequently occur in some familial forms such as lamin A/C mutations. Nonsustained ventricular arrhythmias (VA) are observed in about 40% of patients with DCM, but their prognostic role is not clear, and conflicting data have been published in the last 30 years. Multiple mechanisms can explain atrial and ventricular tachyarrhythmias in DCM. Reentry is associated with slow conduction across surviving muscle bundles within regions of interstitial fibrosis, but other mechanisms can be involved, as nonuniform anisotropy of impulse propagation, ion channel dysfunction, and reduced gap junction function

Ongoing tectonic subsidence in the Lesser Antilles subduction zone

Geological estimates of vertical motions in the central part of the Lesser Antilles show subsidence on timescales ranging from 125.000 to 100 yr, which has been interpreted to be caused by interseismic locking along the subduction megathrust. However, horizontal GNSS velocities show that the Lesser Antilles subduction interface is currently building up little to no elastic strain. Here, we present new present-day vertical velocities for the Lesser Antilles islands and explore the link between short- and long-term vertical motions and their underlying processes. We find a geodetic subsidence of the Lesser Antilles island arc at 1-2 mm yr-1, consistent with the ∼100-yr trend derived from coral micro-atolls. Using elastic dislocation models, we show that a locked or partially locked subduction interface would produce uplift of the island arc, opposite to the observations, hence supporting a poorly coupled subduction. We propose that this long-term, margin-wide subsidence is controlled by slab dynamic processes, such as slab rollback. Such processes could also be responsible for the aseismic character of the subduction megathrust

Ongoing tectonic subsidence in the Lesser Antilles subduction zone

International audienceGeological estimates of vertical motions in the central part of the Lesser Antilles show subsidence on timescales ranging from 125.000 to 100 years, which has been interpreted to be caused by interseismic locking along the subduction megathrust. However, horizontal GNSS velocities show that the Lesser Antilles subduction interface is currently building up little to no elastic strain. Here we present new present-day vertical velocities for the Lesser Antilles islands and explore the link between short- and long-term vertical motions and their underlying processes. We find a geodetic subsidence of the Lesser Antilles island arc at 1-2 mm/yr, consistent with the ~100-year trend derived from coral micro-atolls. Using elastic dislocation models, we show that a locked or partially-locked subduction interface would produce uplift of the island arc, opposite to the observations, hence supporting a poorly-coupled subduction. We propose that this long-term, margin-wide subsidence is controlled by slab dynamic processes, such as slab rollback. Such processes could also be responsible for the aseismic character of the subduction megathrust

Inferring Interseismic Coupling Along the Lesser Antilles Arc: A Bayesian Approach

International audienceThe Lesser Antilles subduction zone is a challenging region when it comes to unraveling its seismogenic behavior. Over the last century, the subduction megathrust has been seismically quiet, with no large thrust event recorded, which raises the question whether this subduction zone is able to produce large interplate earthquakes or not. However, two historical earthquakes in the 19th century, a M 7-8 in 1839 and M 7.5-8.5 in 1843, are proposed to have occurred along the subduction megathrust, although no direct evidence exists. Here we provide a new assessment of interseismic coupling for the Lesser Antilles subduction zone, based on updated Global Positioning System (GPS) velocities and the latest models of the slab geometry and elastic crustal structure. We use a Bayesian approach, allowing us to explore the entire range of plausible models and to provide realistic estimates of interseismic coupling and associated uncertainties. We find low to very low coupling along the entire plate interface, including in the proposed rupture areas of the 1839 and 1843 events, where the sensitivity of our model is high. While a further understanding of temporal variations in interseismic coupling needs to be addressed in future studies, our results indicate that the Lesser Antilles subduction zone is uncoupled, which challenges the idea that the 1839 and 1843 earthquakes were thrust events. The updated GPS velocities of this work now also reveal a small, but detectable amount of along arc extension, consistent with geological observations of active normal faulting within the arc

Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?

Background. With the improvement in genetic testing over time, double-heterozygous mutations are more often found by coincidence in families with hypertrophic cardiomyopathy (HCM). Double heterozygosity can be a cause of the wellknown clinical diversity within HCM families.Methods and results. We describe a family in which members carry either a single mutation or are double heterozygous for mutations in myosin heavy chain gene (MYH7) and cysteine and glycine-rich protein 3 (CSRP3). The described family emphasises the idea of a more severe clinical phenotype with double-heterozygous mutations. It also highlights the importance of cardiological screening where NT-proBNP may serve as an added diagnostic tool.Conclusion. With a more severe inexplicable phenotype of HCM within a family, one should consider the possibility of double-heterozygous mutations. This implies that in such families, even when one disease-causing mutation is found, all the family members still have an implication for cardiological screening parallel to extended genetic screening. (Neth Heart J 2009;17:458-63.

High paleointensities for the Canary Islands constrain the Levant geomagnetic high

Understanding the behavior of enigmatic geomagnetic traits such as the Levant intensity high is currently challenged by a lack of full vector records of regional variations in the geomagnetic field. Here we apply the recently proposed multi-method paleointensity approach to a suite of 19 lavas from the Canary Islands dating between ∼4000 BC and 1909 AD. Our new record reveals high paleointensities (VADMs >120 ZAm2) coinciding with and shortly after the peak in geomagnetic intensity in the Levant at ∼1000 BC. Furthermore our data suggests a westward movement of this geomagnetic phenomenon at a rate of 6.7–12° per century. In addition to IZZI-Thellier, microwave-Thellier and the multi-specimen method, the calibrated pseudo-Thellier method is an important part of the multi-method paleointensity approach. The calibration of this relative paleointensity method was derived from a suite of Hawaiian lavas; it is improved with the results of the Canarian cooling units. Pseudo-Thellier results from samples with very low Curie temperature (<150 °C), however, cannot be reliably converted to absolute paleointensity estimates. The multi-method paleointensity approach yielded a reliable estimate for ∼60% of the flows sampled – an unusually high success rate for a paleointensity study involving lavas

Risk factors for malignant ventricular arrhythmias in lamin A/C mutation carriers a European cohort study

OBJECTIVES: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS: In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS: In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. CONCLUSIONS: Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD

Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers

AIMS: Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality. METHODS AND RESULTS: In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF </=45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3). CONCLUSIONS: This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure