CONCLUSION In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.PURPOSE Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. METHODS Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. RESULTS We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. CONCLUSION The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.PURPOSE Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype. METHODS cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier. RESULTS cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. check details In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy. CONCLUSION cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.Virus taxonomy emerged as a discipline in the middle of the twentieth century. Traditionally, classification by virus taxonomists has been focussed on the grouping of relatively closely related viruses. However, during the past few years, the International Committee on Taxonomy of Viruses (ICTV) has recognized that the taxonomy it develops can be usefully extended to include the basal evolutionary relationships among distantly related viruses. Consequently, the ICTV has changed its Code to allow a 15-rank classification hierarchy that closely aligns with the Linnaean taxonomic system and may accommodate the entire spectrum of genetic divergence in the virosphere. The current taxonomies of three human pathogens, Ebola virus, severe acute respiratory syndrome coronavirus and herpes simplex virus 1 are used to illustrate the impact of the expanded rank structure. This new rank hierarchy of virus taxonomy will stimulate further research on virus origins and evolution, and vice versa, and could promote crosstalk with the taxonomies of cellular organisms.The discovery of Asgard archaea, phylogenetically closer to eukaryotes than other archaea, together with improved knowledge of microbial ecology, impose new constraints on emerging models for the origin of the eukaryotic cell (eukaryogenesis). Long-held views are metamorphosing in favour of symbiogenetic models based on metabolic interactions between archaea and bacteria. These include the classical Searcy's and Hydrogen hypothesis, and the more recent Reverse Flow and Entangle-Engulf-Endogenize models. Two decades ago, we put forward the Syntrophy hypothesis for the origin of eukaryotes based on a tripartite metabolic symbiosis involving a methanogenic archaeon (future nucleus), a fermentative myxobacterial-like deltaproteobacterium (future eukaryotic cytoplasm) and a metabolically versatile methanotrophic alphaproteobacterium (future mitochondrion). A refined version later proposed the evolution of the endomembrane and nuclear membrane system by invagination of the deltaproteobacterial membrane. Here, we adapt the Syntrophy hypothesis to contemporary knowledge, shifting from the original hydrogen and methane-transfer-based symbiosis (HM Syntrophy) to a tripartite hydrogen and sulfur-transfer-based model (HS Syntrophy). We propose a sensible ecological scenario for eukaryogenesis in which eukaryotes originated in early Proterozoic microbial mats from the endosymbiosis of a hydrogen-producing Asgard archaeon within a complex sulfate-reducing deltaproteobacterium. Mitochondria evolved from versatile, facultatively aerobic, sulfide-oxidizing and, potentially, anoxygenic photosynthesizing alphaproteobacterial endosymbionts that recycled sulfur in the consortium. The HS Syntrophy hypothesis accounts for (endo)membrane, nucleus and metabolic evolution in a realistic ecological context. We compare and contrast the HS Syntrophy hypothesis to other models of eukaryogenesis, notably in terms of the mode and tempo of eukaryotic trait evolution, and discuss several model predictions and how these can be tested.The multidrug-resistant Staphylococcus capitis NRCS-A clone is responsible for sepsis in preterm infants in neonatal intensive care units (NICUs) worldwide. Here, to retrace the spread of this clone and to identify drivers of its specific success, we investigated a representative collection of 250 S. capitis isolates from adults and newborns. Bayesian analyses confirmed the spread of the NRCS-A clone and enabled us to date its emergence in the late 1960s and its expansion during the 1980s, coinciding with the establishment of NICUs and the increasing use of vancomycin in these units, respectively. This dynamic was accompanied by the acquisition of mutations in antimicrobial resistance- and bacteriocin-encoding genes. Furthermore, combined statistical tools and a genome-wide association study convergently point to vancomycin resistance as a major driver of NRCS-A success. We also identified another S. capitis subclade (alpha clade) that emerged independently, showing parallel evolution towards NICU specialization and non-susceptibility to vancomycin, indicating convergent evolution in NICU-associated pathogens.