The α/β T cell receptor (TR) is a complex heterodimer that recognizes antigenic peptides and binds to major histocompatibility complex (MH) molecules. Both α and β chains are encoded by different ...genes localized on two distinct chromosomal loci: TRA and TRB. The present study employed the recent release of the swine genome assembly to define the genomic organization of the TRB locus. According to the sequencing data, the pig TRB locus spans approximately 400 kb of genomic DNA and consists of 38 TRBV genes belonging to 24 subgroups located upstream of three in tandem TRBD-J-C clusters, which are followed by a TRBV gene in an inverted transcriptional orientation. Comparative analysis confirms that the general organization of the TRB locus is similar among mammalian species, but the number of germline TRBV genes varies greatly even between species belonging to the same order, determining the diversity and specificity of the immune response. However, sequence analysis of the TRB locus also suggests the presence of blocks of conserved homology in the genomic region across mammals. Furthermore, by analysing a public cDNA collection, we identified the usage pattern of the TRBV, TRBD, and TRBJ genes in the adult pig TRB repertoire, and we noted that the expressed TRBV repertoire seems to be broader and more diverse than the germline repertoire, in line with the presence of a high level of TRBV gene polymorphisms. Because the nucleotide differences seems to be principally concentrated in the CDR2 region, it is reasonable to presume that most T cell β-chain diversity can be related to polymorphisms in pig MH molecules. Domestic pigs represent a valuable animal model as they are even more anatomically, genetically and physiologically similar to humans than are mice. Therefore, present knowledge on the genomic organization of the pig TRB locus allows the collection of increased information on the basic aspects of the porcine immune system and contributes to filling the gaps left by rodent models.
T cells can be separated into two major subsets based on the heterodimer that forms their T cell receptors. αβ T cells have receptors consisting of α and β chains, while γδ T cells are composed of γ ...and δ chains. αβ T cells play an essential role within the adaptive immune responses against pathogens. The recent genomic characterization of the
T cell receptor β (TRB) locus has allowed us to infer the structure of this locus from the draft genome sequences of its wild and domestic Bactrian congeners,
and
. The general structural organization of the wild and domestic Bactrian TRB locus is similar to that of the dromedary, with a pool of TRBV genes positioned at the 5' end of D-J-C clusters, followed by a single TRBV gene located at the 3' end with an inverted transcriptional orientation. Despite the fragmented nature of the assemblies, comparative genomics reveals the existence of a perfect co-linearity between the three Old World camel TRB genomic sequences, which enables the transfer of information from one sequence to another and the filling of gaps in the genomic sequences. A virtual camelid TRB locus is hypothesized with the presence of 33 TRBV genes distributed in 26 subgroups. Likewise, in the artiodactyl species, three in-tandem D-J-C clusters, each composed of one TRBD gene, six or seven TRBJ genes, and one TRBC gene, are placed at the 3' end of the locus. As reported in the ruminant species, a group of four functional TRY genes at the 5' end and only one gene at the 3' end, complete the camelid TRB locus. Although the gene content is similar, differences are observed in the TRBV functional repertoire, and genes that are functional in one species are pseudogenes in the other species. Hence, variations in the functional repertoire between dromedary, wild and domestic Bactrian camels, rather than differences in the gene content, may represent the molecular basis explaining the disparity in the TRB repertoire between the
species. Finally, our data contribute to the knowledge about the evolutionary history of Old World camelids.
WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal ...hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five
rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another
individual. This first report of a
somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with
pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.
These data are presented in support of structural and evolutionary analysis of the published article entitled “The occurrence of three D-J-C clusters within the dromedary TRB locus highlights a ...shared evolution in Tylopoda, Ruminantia and Suina” (Antonacci et al., 2017) 1. Here we describe the genomic structure and the gene content of the T cell receptor beta chain (TRB) locus in Camelus dromedarius. As in the other species of mammals, the general genomic organization of the dromedary TRB locus consists of a pool of TRBV genes located upstream of in tandem TRBD-J-C clusters, followed by a TRBV gene with an inverted transcriptional orientation. A peculiarity of the dromedary TRB locus structure is the presence of three TRBD-J-C clusters, which is a common feature of sheep, cattle and pig sequences.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with ...different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.
Based on the hypothesis that common functional pathways explain comorbidity between diverse neurodevelopmental disorders, we developed an efficient and cost‐effective amplicon‐based multigene panel to assess the pathogenic role of genes involved in intellectual disability (ID) and autism spectrum disorder (ASD) comorbidity. Here, we present the genetic findings after applying this panel to 150 individuals with ID and/or ASD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The αβ T cells are important components of the adaptive immune system and can recognize a vast array of peptides presented by MHC molecules. The ability of these T cells to recognize the complex ...depends on the diversity of the αβ TR, which is generated by a recombination of specific Variable, Diversity and Joining genes for the β chain, and Variable and Joining genes for the α chain. In this study, we analysed the genomic structure and the gene content of the TRB locus in Camelus dromedarius, which is a species belonging to the Tylopoda suborder. The most noteworthy result is the presence of three in tandem TRBD-J-C clusters in the dromedary TRB locus, which is similar to clusters found in sheep, cattle and pigs and suggests a common duplication event occurred prior to the Tylopoda/Ruminantia/Suina divergence. Conversely, a significant contraction of the dromedary TRBV genes, which was previously found in the TRG and TRD loci, was observed with respect to the other artiodactyl species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The Critical Assessment of Genome Interpretation‐5 intellectual disability challenge asked to use computational methods to predict patient clinical phenotypes and the causal variant(s) based on an ...analysis of their gene panel sequence data. Sequence data for 74 genes associated with intellectual disability (ID) and/or autism spectrum disorders (ASD) from a cohort of 150 patients with a range of neurodevelopmental manifestations (i.e. ID, autism, epilepsy, microcephaly, macrocephaly, hypotonia, ataxia) have been made available for this challenge. For each patient, predictors had to report the causative variants and which of the seven phenotypes were present. Since neurodevelopmental disorders are characterized by strong comorbidity, tested individuals often present more than one pathological condition. Considering the overall clinical manifestation of each patient, the correct phenotype has been predicted by at least one group for 93 individuals (62%). ID and ASD were the best predicted among the seven phenotypic traits. Also, causative or potentially pathogenic variants were predicted correctly by at least one group. However, the prediction of the correct causative variant seems to be insufficient to predict the correct phenotype. In some cases, the correct prediction has been supported by rare or common variants in genes different from the causative one.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Objective:
There have been plenty of articles published in recent decades on patient care in the form of case management (CM), but conclusions regarding health outcomes and costs have often ...been discordant. The objective of this study was to examine previous systematic reviews and meta-analyses with a view to assessing and pooling the overwhelming amount of data available on CM-based health outcomes and resource usage.
Methods:
We conducted a review of reviews of secondary studies (meta-analyses and systematic reviews) addressing the effectiveness of CM compared with usual care (or other organizational models) in adult (18+) with long-term conditions. PubMed, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (DARE) were searched from 2000 to the end of December 2017. The outcomes of interest are related to process of care, health measures, and resource usage.
Results:
Twenty-two articles were ultimately considered: 4 meta-analyses and 18 systematic reviews. There is strong evidence of CM increasing adherence to treatment guidelines and improving patient satisfaction, but none of the secondary studies considered demonstrated any effect on patient survival. Based on the available literature, there is contrasting evidence regarding all the other health outcomes, such as quality of life (QOL), clinical outcomes, and functional status. Good-quality secondary studies consistently found nothing to indicate that CM prompts any reduction in the use of hospital resources.
Conclusion:
The source of variability in the literature on the consistency of the evidence for most outcomes is unclear. It may stem from the heterogeneity of CM programs in terms of what their intervention entails, the populations targeted, and the tools used to measure the results. That said, there was consistently strong evidence of CM being associated with a greater adherence to treatment guidelines and higher patient satisfaction, but not with a longer survival or better use of hospital resources.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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