An integrated view of the structure and function of the human 4D nucleome.

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales.

De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems.

Association of genetic and sulcal traits with executive function in congenital heart disease.

Objective: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management.

Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly.

For more than 100 years, the fruit fly has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal.

Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or Obesity.

Background: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD.

A European Survey on Digestive Perianastomotic Ulcerations, a Rare Crohn-like Disorder Occurring in Children and Young Adults.

Objectives: Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat.

Methods: In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU.

De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.

Background: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.

Methods: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD.

Catalytic enantioselective synthesis of perfluoroalkyl-substituted β-lactones a concerted asynchronous [2 + 2] cycloaddition: a synthetic and computational study.

The enantioselective preparation of a range of perfluoroalkyl-substituted β-lactones through an isothiourea (HyperBTM) catalysed reaction using symmetric anhydrides as ammonium enolate precursors and perfluoroalkylketones (R = CF, CF, CF) is reported. Following optimisation, high diastereo- and enantioselectivity was observed for β-lactone formation using CF- and CF-substituted ketones at room temperature (26 examples, up to >95 : 5 dr and >99 : 1 er), whilst -78 °C was necessary for optimal dr and er with CF-substituted ketones (11 examples, up to >95 : 5 dr and >99 : 1 er). Derivatisation of the β-lactones through ring-opening, as well as a two-step conversion to give perfluoroalkyl-substituted oxetanes, is demonstrated without loss of stereochemical integrity.

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes.

The Congenital Heart Disease Genetic Network Study: Cohort description.

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g.

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.

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.

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD.

De novo mutations in histone-modifying genes in congenital heart disease.

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations.

The Congenital Heart Disease Genetic Network Study: rationale, design, and early results.

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD.