Determining the Genetic Contributions of the Williams Syndrome Critical Region to Behavior Using Mouse Models and Human Genetics

Williams syndrome is a neurodevelopmental model caused by the deletion of 26-28 genes on chr7q11.23. The loss of these genes affects multiple organ systems resulting in severe cardiovascular disease, craniofacial dysmorphology, intellectual impairment, a specific Williams syndrome cognitive profile made up of deficits in visual-spatial processing with preserved language skills, and a characteristic hypersocial personality. The reciprocal duplication occurs at a lower frequency and manifests with diametric phenotypes to the deletion. This suggests that this locus harbors dosage sensitive genes that play a role in neurodevelopment. Large efforts have been taken to identify which genes are responsible for causing the different aspects of the disorder. Only the cardiovascular phenotype has been linked to the hemizgosity of the ELN gene. In order to incorporate the complexity of genetic contributions to complex traits, we synthesize genetic and behavioral analyses in both humans and mouse models. We performed whole exome sequencing on 85 individuals with Williams syndrome to test the hypothesis that genetic variation on the remaining chr7q11.23 allele contributes to variation in the social phenotype. We show that the social phenotype consists of deficits in several aspects of social behavior, but social motivation is preserved in Williams syndrome. Whole exome sequencing revealed that there is little common variation contribution to the variability of the social phenotype but did suggest involvement of SNPs in the BAZ1B and GTF2IRD1 genes. Using mouse models, we generated three new mouse lines to test the hypothesis that two genes in the syntenic region, Gtf2i and Gtf2ird1, share overlapping DNA targets and both contribute to overlapping behavioral phenotypes suggesting an oligogenic contribution of these genes to phenotypes relevant to WS. Finally, we show that loss of function mutations in both Gtf2i and Gtf2ird1 are not sufficient to reproduce the full phenotype that is produced by deleting the entire syntenic Williams syndrome critical region in mice. Taken together these data suggest an oligogenic pattern of contribution to the phenotypes seen in WS

Moving from capstones toward cornerstones: Successes and challenges in applying systems biology to identify mechanisms of autism spectrum disorders

The substantial progress in the last few years toward uncovering genetic causes and risk factors for autism spectrum disorders (ASDs) has opened new experimental avenues for identifying the underlying neurobiological mechanism of the condition. The bounty of genetic findings has led to a variety of data-driven exploratory analyses aimed at deriving new insights about the shared features of these genes. These approaches leverage data from a variety of different sources such as co-expression in transcriptomic studies, protein-protein interaction networks, gene ontologies (GOs) annotations, or multi-level combinations of all of these. Here, we review the recurrent themes emerging from these analyses and highlight some of the challenges going forward. Themes include findings that ASD associated genes discovered by a variety of methods have been shown to contain disproportionate amounts of neurite outgrowth/cytoskeletal, synaptic, and more recently Wnt-related and chromatin modifying genes. Expression studies have highlighted a disproportionate expression of ASD gene sets during mid fetal cortical development, particularly for rare variants, with multiple analyses highlighting the striatum and cortical projection and interneurons as well. While these explorations have highlighted potentially interesting relationships among these ASD-related genes, there are challenges in how to best transition these insights into empirically testable hypotheses. Nonetheless, defining shared molecular or cellular pathology downstream of the diverse genes associated with ASDs could provide the cornerstones needed to build toward broadly applicable therapeutic approaches

Wandering Gallbladder: A Case Report

Wandering gallbladder is a variation in the biliary anatomy described in the literature as being attached only by the cystic duct and its mesentery. Its propensity for torsion places it at risk for necrosis. There have been over 500 cases of gallbladder torsion reported in the literature but less than 10 reports of wandering gallbladder. To our knowledge there have been no reports of cholecystectomy for wandering gallbladder found incidentally. A 51-year-old male from Pakistan with hypertension, gastroesophageal reflux disease, high cholesterol, and renal stones presented with a chief complaint of right upper quadrant abdominal pain. Abdominal ultrasound was significant for a mildly distended gallbladder with small gallstones in the gallbladder fundus. The patient was discharged with a diagnosis of cholelithiasis and scheduled for laparoscopic cholecystectomy as an outpatient. During the procedure, upon entering the abdominal cavity, a gallbladder was not seen in the gallbladder fossa. It was attached to the cystic duct, thickened with a long mesentery and not attached to the liver. There were no signs of torsion. The patient was treated successfully and discharged home with an uncomplicated hospital course. Diagnosis can be challenging because the clinical presentation can be variable. Fewer than a dozen cases have been reported where the diagnosis was made preoperatively. Early diagnosis of gallbladder torsion with cholecystectomy is essential to avoid the deadly complications of perforation and bilious peritonitis. Understanding the pathophysiology, clinical findings, and treatment can have a broad impact across biliary surgery in preventing these complications

Determining the Genetic Contributions of the Williams Syndrome Critical Region to Behavior Using Mouse Models and Human Genetics

Williams syndrome is a neurodevelopmental model caused by the deletion of 26-28 genes on chr7q11.23. The loss of these genes affects multiple organ systems resulting in severe cardiovascular disease, craniofacial dysmorphology, intellectual impairment, a specific Williams syndrome cognitive profile made up of deficits in visual-spatial processing with preserved language skills, and a characteristic hypersocial personality. The reciprocal duplication occurs at a lower frequency and manifests with diametric phenotypes to the deletion. This suggests that this locus harbors dosage sensitive genes that play a role in neurodevelopment. Large efforts have been taken to identify which genes are responsible for causing the different aspects of the disorder. Only the cardiovascular phenotype has been linked to the hemizgosity of the ELN gene. In order to incorporate the complexity of genetic contributions to complex traits, we synthesize genetic and behavioral analyses in both humans and mouse models. We performed whole exome sequencing on 85 individuals with Williams syndrome to test the hypothesis that genetic variation on the remaining chr7q11.23 allele contributes to variation in the social phenotype. We show that the social phenotype consists of deficits in several aspects of social behavior, but social motivation is preserved in Williams syndrome. Whole exome sequencing revealed that there is little common variation contribution to the variability of the social phenotype but did suggest involvement of SNPs in the BAZ1B and GTF2IRD1 genes. Using mouse models, we generated three new mouse lines to test the hypothesis that two genes in the syntenic region, Gtf2i and Gtf2ird1, share overlapping DNA targets and both contribute to overlapping behavioral phenotypes suggesting an oligogenic contribution of these genes to phenotypes relevant to WS. Finally, we show that loss of function mutations in both Gtf2i and Gtf2ird1 are not sufficient to reproduce the full phenotype that is produced by deleting the entire syntenic Williams syndrome critical region in mice. Taken together these data suggest an oligogenic pattern of contribution to the phenotypes seen in WS

The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ uptake

Background and Purpose The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage‐dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevin–VDAC2 interaction. Experimental Approach To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligand‐protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevin‐induced modulation of VDAC2 were analysed in HL‐1 cardiomyocytes. Key Results In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion‐selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore‐lining N‐terminal α‐helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin‐responsiveness. Upon heterologous expression in HL‐1 cardiomyocytes, both channels, wild‐type VDAC2 and the efsevin‐insensitive VDAC2AAA restored mitochondrial Ca2+ uptake, but only wild‐type VDAC2 was sensitive to efsevin. Conclusion and Implications In summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR‐mitochondria Ca2+ transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure‐aided chemical optimization of efsevin

The anatomical distribution of genetic associations

Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count – a quantitative trait of the immune system – is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues

Human iPSC-derived neurons and cerebral organoids establish differential effects of germline NF1 gene mutations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability

Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

PURPOSE These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. METHODS We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. RESULTS From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. CONCLUSIONS We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care

Highly selective, reversible water activation by P,N-cooperativity in pyridyl-functionalized phosphinines

Tetrapyridyl-functionalized phosphinines were prepared and structurally characterized. The donor-functionalized aromatic phosphorus heterocycles react highly selectively and even reversibly with water. Calculations reveal P,N-cooperativity for this process, with the flanking pyridyl groups serving to kinetically enhance the formal oxidative addition process of H2O to the low-coordinate phosphorus atom via H-bonding. Subsequent tautomerization forms 1,2-dihydrophosphinine derivatives, which can be quantitatively converted back to the phosphinine by applying vacuum, even at room temperature. This process can be repeated numerous times, without any sign of decomposition of the phosphinine. In the presence of CuI·SMe2, dimeric species of the type ([Cu2I2(phosphinine)]2) are formed, in which each phosphorus atom shows the less common μ2-bridging 2e−-lone-pair-donation to two Cu(i)-centres. Our results demonstrate that fully unsaturated phosphorus heterocycles, containing reactive P = C double bonds, are interesting candidates for the activation of E-H bonds, while the aromaticity of such compounds plays an appreciable role in the reversibility of the reaction, supported by NICS calculations