Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Purpose We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Methods Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. Results We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. Conclusion In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome

"Mushroom cloud": a giant left ventricular pseudoaneurysm after a myocardial infarction due to myocardial bridging – a case report

Left ventricular pseudoaneurysm is an uncommon complication after transmural myocardial infarction, occurring when a free wall rupture is contained by adhesions of the overlying pericardium preventing acute tamponade. In this report, an unusual case of a 61 year-old male with a giant apical left ventricular pseudoaneurysm after an unnoticed myocardial infarction is presented. On coronary angiogram myocardial bridging of the distal left anterior descending artery was judged to be the infarct related lesion. The echocardiographic diagnosis allowed for a timely surgical intervention which resulted in the patient's full recovery

Author Correction: Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

Correction to: Nature Genetics https://doi.org/10.1038/s41588-019-0564-y, published online 05 February 2020

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder

Author Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing (Nature Genetics, (2020), 52, 3, (331-341), 10.1038/s41588-019-0576-7)

Correction to: Nature Genetics, published online 05 February 2020. In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper

Absent B Cells, agammaglobulinemia, and Hypertrophic Cardiomyopathy in Folliculin-interacting Protein 1 Deficiency

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity

Editorial of Special Issue of National Identities: Alevism as an ethno-religious identity: Contested boundaries

No abstract for editorial but this is the opening paragraph: This special issue on Alevism and trans/national Alevi identity critically engages with the relationship between religion, ethnicity and national identity. The core issues are as follows: • how ethnicity and religion are conceptualised for a relatively invisible ethnic group in different national contexts; • how religion and ethnicity intersect when Alevism is both a faith and an ethnic identity, especially when conceptions of that identity are contested; • how identity is shaped through state policies within different national policy contexts and how etic definitions of minority communities are constructed by the state or other agencies with the power to impose them on the community in contrast to the emic or self-definitions of Aleviness from within the Alevi community; • how despite the fragmented, heterogeneous nature of Alevi communities, there is also a sense of a single, transnational imaginary community, at least for the purposes of political assimilation/integration and activism; • how education and other arenas of political, religious and cultural engagement at local, national and transnational levels create the possibilities, both positively and negatively, for future action/policy to situate minority ethnic communities

Steroid Hormone Control of Cell Death and Cell Survival: Molecular Insights Using RNAi

The insect steroid hormone ecdysone triggers programmed cell death of obsolete larval tissues during metamorphosis and provides a model system for understanding steroid hormone control of cell death and cell survival. Previous genome-wide expression studies of Drosophila larval salivary glands resulted in the identification of many genes associated with ecdysone-induced cell death and cell survival, but functional verification was lacking. In this study, we test functionally 460 of these genes using RNA interference in ecdysone-treated Drosophila l(2)mbn cells. Cell viability, cell morphology, cell proliferation, and apoptosis assays confirmed the effects of known genes and additionally resulted in the identification of six new pro-death related genes, including sorting nexin-like gene SH3PX1 and Sox box protein Sox14, and 18 new pro-survival genes. Identified genes were further characterized to determine their ecdysone dependency and potential function in cell death regulation. We found that the pro-survival function of five genes (Ras85D, Cp1, CG13784, CG32016, and CG33087), was dependent on ecdysone signaling. The TUNEL assay revealed an additional two genes (Kap-α3 and Smr) with an ecdysone-dependent cell survival function that was associated with reduced cell death. In vitro, Sox14 RNAi reduced the percentage of TUNEL-positive l(2)mbn cells (p<0.05) following ecdysone treatment, and Sox14 overexpression was sufficient to induce apoptosis. In vivo analyses of Sox14-RNAi animals revealed multiple phenotypes characteristic of aberrant or reduced ecdysone signaling, including defects in larval midgut and salivary gland destruction. These studies identify Sox14 as a positive regulator of ecdysone-mediated cell death and provide new insights into the molecular mechanisms underlying the ecdysone signaling network governing cell death and cell survival

Galectin-3 and Beclin1/Atg6 Genes In Human Cancers: Using cDNA Tissue Panel, qRT-PCR, and Logistic Regression Model to Identify Cancer Cell Biomarkers

Cancer biomarkers are sought to support cancer diagnosis, predict cancer patient response to treatment and survival. Identifying reliable biomarkers for predicting cancer treatment response needs understanding of all aspects of cancer cell death and survival. Galectin-3 and Beclin1 are involved in two coordinated pathways of programmed cell death, apoptosis and autophagy and are linked to necroptosis/necrosis. The aim of the study was to quantify galectin-3 and Beclin1 mRNA in human cancer tissue cDNA panels and determine their utility as biomarkers of cancer cell survival.A panel of 96 cDNAs from eight (8) different normal and cancer tissue types were used for quantitative real-time polymerase chain reaction (qRT-PCR) using ABI7900HT. Miner2.0, a web-based 4- and 3-parameter logistic regression software was used to derive individual well polymerase chain reaction efficiencies (E) and cycle threshold (Ct) values. Miner software derived formula was used to calculate mRNA levels and then fold changes. The ratios of cancer to normal tissue levels of galectin-3 and Beclin1 were calculated (using the mean for each tissue type). Relative mRNA expressions for galectin-3 were higher than for Beclin1 in all tissue (normal and cancer) types. In cancer tissues, breast, kidney, thyroid and prostate had the highest galectin-3 mRNA levels compared to normal tissues. High levels of Beclin1 mRNA levels were in liver and prostate cancers when compared to normal tissues. Breast, kidney and thyroid cancers had high galectin-3 levels and low Beclin1 levels.Galectin-3 expression patterns in normal and cancer tissues support its reported roles in human cancer. Beclin1 expression pattern supports its roles in cancer cell survival and in treatment response. qRT-PCR analysis method used may enable high throughput studies to generate molecular biomarker sets for diagnosis and predicting cancer treatment response

Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers

Correction to: Nature Genetics, published online 05 February 2020. In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper