ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype

Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi-commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Optical Properties of Five Esthetic Ceramic Materials Used for Monolithic Restorations: A Comparative In Vitro Study

Zirconia has generated tremendous interest in the esthetic materials used for dental restorations. However, using conventional zirconia has some limitations especially in highly esthetically demanding situations, as it lacks the translucency that other ceramic materials possess. This study aimed to evaluate and compare the optical properties (shade, translucency, and opalescence) of three CAD-CAM monolithic multilayer zirconia ceramics (GNX; Ceramill Zolid® Gen-X, ZCP; IPS e.max® ZirCAD, and UPC; Upcera® Esthetic Explore Prime) and one CAD-CAM monolithic multilayer polymer-infiltrated hybrid ceramic (ENM; Vita® Enamic) with a CAD-CAM monolithic lithium disilicate ceramic as control (EMX; IPS e.max® CAD). 200 discs (GNX = 40, ZCP = 40, UPC = 40, ENM = 40, and EMX = 40) were cut, polished, and fully crystallized. Half of the samples for each group were subjected to hydrothermal aging. Descriptive analysis and ANOVA tests were used to compare the groups. Zirconia GNX, ZCP, and UPC groups showed significantly lower optical properties than ENM and EMX groups for both the non-aged and aged samples (p p < 0.05). The optical properties of monolithic multilayer zirconia ceramics were lower than monolithic multilayer polymer-infiltrated hybrid ceramic and lithium disilicate ceramic. Polymer-infiltrated hybrid ceramic was significantly affected by aging

Mechanical Properties of Five Esthetic Ceramic Materials Used for Monolithic Restorations: A Comparative In Vitro Study

Monolithic zirconia and hybrid ceramic restorations have been widely used in the last decade for both anterior and posterior dental restorations. However, their use lacks sufficient scientific evidence in most cases, as the expeditious manufacturing of these versatile ceramic materials exceeds the limits of in vitro and/or in vivo validation. This study aimed to evaluate and compare the mechanical properties (flexural strength, fracture toughness, Vickers hardness, and brittleness index) of three CAD-CAM monolithic multilayer zirconia ceramics (GNX—Ceramill Zolid® Gen-X, ZCP—IPS e.max® ZirCAD, and UPC—Upcera® Esthetic Explore Prime) and one CAD-CAM monolithic multilayer polymer-infiltrated hybrid ceramic (ENM—Vita® Enamic) with a CAD-CAM monolithic lithium disilicate ceramic as a control (EMX —IPS e.max® CAD). A total of 160 discs (GNX = 32, ZCP = 32, UPC = 32, ENM = 32, and EMX = 32) were cut, polished, and fully sintered (except for the ENM). Half of the samples for each group were subjected to hydrothermal aging. Descriptive analysis and ANOVA tests were used to compare the groups. The zirconia groups showed significantly higher mechanical properties than the EMX group for both the non-aged and aged samples (p < 0.05). The ENM group showed the lowest brittleness index, while EMX showed the highest. The mechanical properties of monolithic multilayer zirconia ceramics were generally better than those of monolithic multilayer polymer-infiltrated hybrid ceramic and lithium disilicate ceramic. All groups showed, to some extent, a change in their mechanical properties after aging, with the ENM being the most affected

Optical Properties of Five Esthetic Ceramic Materials Used for Monolithic Restorations: A Comparative In Vitro Study

Zirconia has generated tremendous interest in the esthetic materials used for dental restorations. However, using conventional zirconia has some limitations especially in highly esthetically demanding situations, as it lacks the translucency that other ceramic materials possess. This study aimed to evaluate and compare the optical properties (shade, translucency, and opalescence) of three CAD-CAM monolithic multilayer zirconia ceramics (GNX; Ceramill Zolid&reg; Gen-X, ZCP; IPS e.max&reg; ZirCAD, and UPC; Upcera&reg; Esthetic Explore Prime) and one CAD-CAM monolithic multilayer polymer-infiltrated hybrid ceramic (ENM; Vita&reg; Enamic) with a CAD-CAM monolithic lithium disilicate ceramic as control (EMX; IPS e.max&reg; CAD). 200 discs (GNX = 40, ZCP = 40, UPC = 40, ENM = 40, and EMX = 40) were cut, polished, and fully crystallized. Half of the samples for each group were subjected to hydrothermal aging. Descriptive analysis and ANOVA tests were used to compare the groups. Zirconia GNX, ZCP, and UPC groups showed significantly lower optical properties than ENM and EMX groups for both the non-aged and aged samples (p &lt; 0.05). UPC and ENM groups showed a significant decrease in translucency and opalescence after aging (p &lt; 0.05). The optical properties of monolithic multilayer zirconia ceramics were lower than monolithic multilayer polymer-infiltrated hybrid ceramic and lithium disilicate ceramic. Polymer-infiltrated hybrid ceramic was significantly affected by aging