Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of ...common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.
BACKGROUND:Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely ...tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
METHODS:Utilizing an evidence-based framework, 3 gene curation teams blinded to each other’s work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
RESULTS:Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS.
CONCLUSIONS:More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
Abstract
We report on the investigation and observation of Bloch surface wave polaritons, resulting from the interaction between excitons in ZnO and a Bloch surface wave supported by a distributed ...Bragg reflector (DBR), for temperatures up to 430 K. The samples were fabricated using pulsed laser deposition and consist of a DBR made of 6.5 layer pairs of yttrica-stabilized zirconia and Al
2
O
3
with a ZnO surface layer. We measured the reflectivity of transverse electric modes using a SiO
2
prism in Kretschmann–Raether configuration, giving access to high in-plane momenta. Whereas the lower polariton branch was clearly observable, the upper polariton branch was not visible, due to the strong absorption in ZnO above the excitonic resonance. By employing a coupled oscillator model for the interaction between the bare surface mode and exciton, we derived a corresponding Rabi splitting between 100–192 meV at 294 K, which decreases with increasing temperature.
A hybrid approach to solar cells is demonstrated in which a silicon p–n junction, used in conventional silicon‐based photovoltaics, is replaced by a room‐temperature fabricated silicon/organic ...heterojunction. The unique advantage of silicon/organic heterojunction is that it exploits the cost advantage of organic semiconductors and the performance advantages of silicon to enable potentially low‐cost, efficient solar cells.
We report on a microfluidic particle-separation device that makes use of the asymmetric bifurcation of laminar flow around obstacles. A particle chooses its path deterministically on the basis of its ...size. All particles of a given size follow equivalent migration paths, leading to high resolution. The microspheres of 0.8, 0.9, and 1.0 micrometers that were used to characterize the device were sorted in 40 seconds with a resolution of ~10 nanometers, which was better than the time and resolution of conventional flow techniques. Bacterial artificial chromosomes could be separated in 10 minutes with a resolution of ~12%.
Quantum fluids based on light is a highly developing research field, since they provide a nonlinear platform for developing optical functionalities and quantum simulators. An important issue in this ...context is the ability to coherently control the properties of the fluid. Here we propose an all-optical approach for controlling the phase of a flow of cavity-polaritons, making use of their strong interactions with localized excitons. Here we illustrate the potential of this method by implementing a compact exciton-polariton interferometer, which output intensity and polarization can be optically controlled. This interferometer is cascadable with already reported polariton devices and is promising for future polaritonic quantum optic experiments. Complex phase patterns could be also engineered using this optical method, providing a key tool to build photonic artificial gauge fields.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to ...cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.
Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).
Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) ...individuals is unclear. We investigated associations of “restricted” and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRSTikkanen and PRSTada; 28 and 50 variants, respectively) and two genome-wide PRSs (PRSmetaGRS and PRSLDPred; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRSmetaGRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46–1.60), 1.53 (1.23–1.90), and 1.27 (1.13–1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (pinteraction = 0.77) but were significantly attenuated in AA individuals (pinteraction= 2.9 × 10−3). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.
Photonic bandgap crystals can reflect light for any direction of propagation in specific wavelength ranges. This property, which can be used to confine, manipulate and guide photons, should allow the ...creation of all-optical integrated circuits. To achieve this goal, conventional semiconductor nanofabrication techniques have been adapted to make photonic crystals. A potentially simpler and cheaper approach for creating three-dimensional periodic structures is the natural assembly of colloidal microspheres. However, this approach yields irregular, polycrystalline photonic crystals that are difficult to incorporate into a device. More importantly, it leads to many structural defects that can destroy the photonic bandgap. Here we show that by assembling a thin layer of colloidal spheres on a silicon substrate, we can obtain planar, single-crystalline silicon photonic crystals that have defect densities sufficiently low that the bandgap survives. As expected from theory, we observe unity reflectance in two crystalline directions of our photonic crystals around a wavelength of 1.3 micrometres. We also show that additional fabrication steps, intentional doping and patterning, can be performed, so demonstrating the potential for specific device applications.
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