Genomic characterization is an essential part of the clinical management of hematological malignancies for diagnostic, prognostic and therapeutic purposes. Although CBA and FISH are still the gold ...standard in hematology for the detection of CNA and SV, some alternative technologies are intended to complement their deficiencies or even replace them in the more or less near future. In this article, we provide a technological overview of these alternatives. CMA is the historical and well established technique for the high-resolution detection of CNA. For SV detection, there are emerging techniques based on the study of chromatin conformation and more established ones such as RTMLPA for the detection of fusion transcripts and RNA-seq to reveal the molecular consequences of SV. Comprehensive techniques that detect both CNA and SV are the most interesting because they provide all the information in a single examination. Among these, OGM is a promising emerging higher-solution technique that offers a complete solution at a contained cost, at the expense of a relatively low throughput per machine. WGS remains the most adaptable solution, with long-read approaches enabling very high-resolution detection of CAs, but requiring a heavy bioinformatics installation and at a still high cost. However, the development of high-resolution genome-wide detection techniques for CAs allows for a much better description of chromoanagenesis. Therefore, we have included in this review an update on the various existing mechanisms and their consequences and implications, especially prognostic, in hematological malignancies.
Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour ...two functional modules/complexes (Meckel syndrome MKS and Nephronophthisis NPHP) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ.
During June 2017-April 2018, active tuberculosis with Beijing SIT1 isolates was diagnosed in 14 persons living in 4 distant cities in France. Whole-genome sequencing indicated that these patients ...belonged to a single transmission chain. Whole-genome sequencing-based laboratory investigations enabled prompt tracing of linked cases to improve tuberculosis control.
Abstract
With the dramatic increase of pangenomic analysis, Human geneticists have generated large amount of genomic data including millions of small variants (SNV/indel) but also thousands of ...structural variations (SV) mainly from next-generation sequencing and array-based techniques. While the identification of the complete SV repertoire of a patient is getting possible, the interpretation of each SV remains challenging. To help identifying human pathogenic SV, we have developed a web server dedicated to their annotation and ranking (AnnotSV) as well as their visualization and interpretation (knotAnnotSV) freely available at the following address: https://www.lbgi.fr/AnnotSV/. A large amount of annotations from >20 sources is integrated in our web server including among others genes, haploinsufficiency, triplosensitivity, regulatory elements, known pathogenic or benign genomic regions, phenotypic data. An ACMG/ClinGen compliant prioritization module allows the scoring and the ranking of SV into 5 SV classes from pathogenic to benign. Finally, the visualization interface displays the annotated SV in an interactive way including popups, search fields, filtering options, advanced colouring to highlight pathogenic SV and hyperlinks to the UCSC genome browser or other public databases. This web server is designed for diagnostic and research analysis by providing important resources to the user.
Graphical Abstract
Graphical Abstract
Here we present a web server dedicated to the annotation and ranking of structural variations (AnnotSV) as well as their visualization and interpretation (knotAnnotSV).
Thermococcus gammatolerans EJ3 is an extremophile archaeon which was revealed as one of the most radioresistant organisms known on Earth, withstanding up to 30 kGy gamma-ray radiations. While its ...theoretical proteome is rather small, T. gammatolerans may enhance its toolbox by post-translational modification of its proteins. Here, we explored its extent of Nε-acetylation of lysines. For this, we immunopurified with two acetylated-lysine antibodies the acetylated peptides resulting from a proteolysis of soluble proteins with trypsin. The comparison of acetylated proteomes of two archaea highlights some common acetylation patterns but only 4 out of 26 orthologous proteins found to be acetylated in both species, are acetylated on the same lysine site. We evidenced that histone B is acetylated in T. gammatolerans at least at two different sites (K27 and K36), and a peptide common at the C-terminus of histones A and B is also acetylated. We verified that acetylation of histones is a common trait among Thermococcales after recording data on Thermococcus kodakaraensis histones and identifying three acetylated sites. This discovery reinforces the strong evolutionary link between Archaea and Eukaryotes and should be an incentive for further investigation on the extent and role of acetylation of histones in Archaea.
Acetylation is an important post-translational modification of proteins that has been extensively described in Eukaryotes, and more recently in Bacteria. Here, we report for the first time ever that histones in Archaea are also modified by acetylation after a systematic survey of acetylated peptides in Thermococcus gammatolerans. Structural models of histones A and B indicates that acetylation of the identified modified residues may play an important role in histone assembly and/or interaction with DNA. The in-depth protein acetylome landscape in T. gammatolerans includes at least 181 unique protein sequences, some of them being modified on numerous residues. Proteins involved in metabolic processes, information storage and processing mechanisms are over-represented categories in this dataset, highlighting the ancient role of this protein post-translational modification in primitive cells.
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•We identified 338 acetylated sites by mass spectrometry.•Some common acetylation patterns are found among archaea.•Histones from two different archaea were evidenced for the first time to be acetylated.•Structural models of histones A and B indicates that acetylation may play a key role.
Objective
We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.
Methods
We ...retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams‐Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.
Results
40 fetuses with WBS were collected and the most common features were intra‐uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.
Conclusion
This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.
Key points
What is already known on this topic?
Deletion of the 7q11.23 region causes the Williams Beuren syndrome (WBS). The reciprocal duplication is responsible for a distinctive although less severe neurodevelopmental disorder.
Diagnosis of WBS is usually suspected postnatally in infants but its prenatal presentation remains challenging.
What does this study add?
Largest series of fetuses with a 7q11.23 deletion or a 7q11.23 duplication.
Antenatal ultrasound findings of prenatal 7q11.23 copy number variations.
•Twinning-induced plasticity (TWIP) strategy was first applied in zr alloys for strain-hardening and ductility enhancements.•Zr-13.8Nb-0.7Hf and Zr-15.5Nb-0.7Hf alloys designed by electron-to-atom ...ratio exhibit multi-phase microstructures consisting of acicular body-centered tetragonal phase and monoclinic phase in beta grains.•TWIP-enhanced Zr-13.8Nb-0.7Hf alloy resulted in superior strain-hardening rate and ductility when comparing to Zr-15.5Nb-0.7Hf without mechanical twinning.•In-situ traction tests in TEM and SEM-EBSD were conducted to clarify the {332} twinning operation and its interaction with body-centered tetragonal phase.
The deformation mechanisms were studied in metastable Zr-13.8Nb-0.7Hf and Zr-15.5Nb-0.7Hf (wt.%) alloys exhibiting complex microstructures due to quenched-in precipitates (acicular body-centered tetragonal phase and globular monoclinic phase) in beta grains. Twinning-induced plasticity (TWIP) effect was observed in Zr-13.8Nb-0.7Hf via {332} twinning operation, resulting in higher strain-hardening rate and uniform elongation than those of Zr-15.5Nb-0.7Hf deforming via only dislocation glide. In-situ characterizations, by applying tensile deformation during electron backscattered diffraction (EBSD) mapping and transmission electron microscopy (TEM) observation, were conducted to clarify the twinning process and the role of quenched-in precipitates when interacting with deformation twins.
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What is already known about this subject?
Non invasive prenatal testing for fetal trisomies 13, 18, and 21 occasionally identifies maternal cancer.
What does this study add?
A further case of ...maternal cancer incidentally diagnosed by routine NIPT.
Extensive NIPT abnormalities are unlikely to be of fetal origin.
Information given to patients should also adequately advise patients on potential incidental findings and might offer the option to opt out of receiving results beyond the trisomy report.
International guidelines would improve patient counseling.
Summary
A translocation involving the cyclin‐dependent kinase 6 (CDK6) gene t(CDK6) is a rare but recurrent abnormality in B‐cell neoplasms. To further characterise this aberration, we studied 57 ...cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T‐cell receptor alpha locus (TRA)/T‐cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B‐cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B‐cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus‐associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy‐chain variable‐region (IGHV) locus sequencing revealed that none harboured an IGHV1‐02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B‐cell lymphomas with distinctive features.
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