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PubMed | Center Intercommunal Poissy St Germain en Laye, Clinique Pasteur, Service de Cardiologie Pediatrique, Pediatrie Cardiologie and 11 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ), NKX2-5 (6 ), ZIC3 (3 ), MLPA (2 ) and ELN (4 ). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.


Bogaerts P.,Cliniques Universitaires | Naas T.,University Paris - Sud | El Garch F.,Cliniques Universitaires | Cuzon G.,University Paris - Sud | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

During a PCR-based surveillance study of β-lactam resistance, 125 multidrug-resistant (MDR) Acinetobacter baumannii isolates were obtained from 18 hospitals in Belgium from January 2008 to December 2009. Nine GES-positive A. baumannii isolates were detected at 6 Belgian hospitals. DNA sequencing of the blaGES genes identified GES-11, GES-12, and a novel variant GES-14, which differs from GES-11 by a single amino acid substitution (Gly170Ser). All index isolates were travel associated and originated from patients transferred from Turkey (n = 2), Egypt (n = 2), and Palestinian territories (Gaza) (n = 2). A nosocomial outbreak involving three additional patients occurred in a burn unit at a single hospital. No clonal relatedness could be established between the 6 index isolates by pulsed-field gel electrophoresis (PFGE) analysis. Three different alleles (the plasmid-located blaGES-11 and bla GES-12 and a likely chromosomally located novel variant bla GES-14) were detected as part of a class 1 integron, also including the aac6′Ib and dfrA7 genes. Restriction analysis of plasmids suggests a common origin for the plasmids bearing blaGES-11 and bla GES-12. Cloning of the blaGES genes in Escherichia coli identified GES-14 as hydrolyzing imipenem, while GES-12 showed the highest specific activity against ceftazidime. This report highlights the emergence of various blaGES-like genes, especially those conferring carbapenem resistance in A. baumannii and its importation in Western Europe from Middle Eastern countries. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Koeck J.-L.,Laboratoire Of Biologie Clinique | Fabre M.,Laboratoire Of Biologie Clinique | Simon F.,Service des maladies infectieuses et tropicales | Daffe M.,CNRS Institute of Pharmacology and Structural Biology | And 6 more authors.
Clinical Microbiology and Infection | Year: 2011

Over a 3-year follow-up, 30 out of the 318 unique Mycobacterium tuberculosis complex isolates recovered in the Republic of Djibouti had a smooth-type morphology and were Niacine-negative, the characteristics of 'Mycobacterium canettii' strains. Unlike M. tuberculosis, 'M. canettii' grew on nutrient-poor media at 30°C, and possessed characteristic lipids. They were isolated from respiratory and extra-respiratory sites from patients with typical forms of tuberculosis. Most cases resolved with antibiotic therapy but in two human immunodeficiency virus-positive patients 'M. canettii' infection led to septicaemia and death. No cases of human-to-human transmission were observed. The proportion of tuberculosis cases caused by 'M. canettii' was higher among French patients than among Djiboutian patients. Patients with 'M. canettii' were significantly younger than those with tuberculosis caused by other M. tuberculosis complex strains. Smooth tubercle bacilli could be misidentified as non-tuberculous mycobacteria and appear to be limited to the Horn of Africa. Their characteristics are consistent with the existence of non-human sources of infection. © 2010 The Authors. Clinical Microbiology and Infection © 2010 European Society of Clinical Microbiology and Infectious Diseases.


Fabre M.,Laboratoire Of Biologie Clinique | Hauck Y.,University Paris - Sud | Soler C.,Laboratoire Of Biologie Clinique | Koeck J.-L.,Laboratoire Of Biologie Clinique | And 5 more authors.
Infection, Genetics and Evolution | Year: 2010

Since the first discovery of the smooth tubercle (SmTB) bacilli "Mycobacterium canettii" less than 60 isolates have been reported, all but one originating from a limited geographical location, the Horn of Africa. In spite of its rarity, the SmTB lineage deserves special attention. Previous investigations suggested that SmTB isolates represent an ancestral lineage of the Mycobacterium tuberculosis complex (MTBC) and that consequently they might provide essential clues on the origin and evolution of the MTBC. There is evidence that unlike the rest of the MTBC, SmTB strains recombine chromosomal sequences with a yet unknown Mycobacterium species. This behavior contributes to the much larger genetic heterogeneity observed in the SmTB isolates compared to the other members of the MTBC. We have collected 59 SmTB isolates of which 14 were newly recovered since previous reports, and performed extensive phenotypical and genotypical characterization. We take advantage of these investigations to review the current knowledge of "M. canettii" Their characteristics and the apparent lack of human to human transmission are consistent with the previously proposed existence of non-human sources of infection. SmTB strains show remarkably common features together with secondary and taxonomically minor genetic differences such as the presence or absence of the CRISPR (Clustered Regularly Interspersed Palindromic Repeat) locus (usually called Direct Repeat or DR region) or number of IS sequences. Multiple Locus Variable number of tandem repeat Analysis (MLVA) and DR region analyses reveal one predominant clone, one minor clone and a number of more distantly related strains. This suggests that the two most frequent clones may represent successfully emerging lineages. © 2010 Elsevier B.V.


Hauck Y.,University Paris - Sud | Hauck Y.,French National Center for Scientific Research | Soler C.,Laboratoire Of Biologie Clinique | Jault P.,Laboratoire Of Biologie Clinique | And 11 more authors.
PLoS ONE | Year: 2012

Background: Infections by A. calcoaceticus-A. baumannii (ACB) complex isolates represent a serious threat for wounded and burn patients. Three international multidrug-resistant (MDR) clones (EU clone I-III) are responsible for a large proportion of nosocomial infections with A. baumannii but other emerging strains with high epidemic potential also occur. Methodology/Principal Findings: We automatized a Multiple locus variable number of tandem repeats (VNTR) analysis (MLVA) protocol and used it to investigate the genetic diversity of 136 ACB isolates from four military hospitals and one childrens hospital. Acinetobacter sp other than baumannii isolates represented 22.6% (31/137) with a majority being A. pittii. The genotyping protocol designed for A.baumannii was also efficient to cluster A. pittii isolates. Fifty-five percent of A. baumannii isolates belonged to the two international clones I and II, and we identified new clones which members were found in the different hospitals. Analysis of two CRISPR-cas systems helped define two clonal complexes and provided phylogenetic information to help trace back their emergence. Conclusions/Significance: The increasing occurrence of A. baumannii infections in the hospital calls for measures to rapidly characterize the isolates and identify emerging clones. The automatized MLVA protocol can be the instrument for such surveys. In addition, the investigation of CRISPR/cas systems may give important keys to understand the evolution of some highly successful clonal complexes. © 2012 Hauck et al.


Supply P.,French Institute of Health and Medical Research | Supply P.,French National Center for Scientific Research | Supply P.,University of Lille Nord de France | Supply P.,Institute Pasteur Of Lille | And 64 more authors.
Nature Genetics | Year: 2013

Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5× coverage), 454/Roche (13-18× coverage) and/or Illumina DNA sequencing (45-105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved. © 2013 Nature America, Inc. All rights reserved.


Namouchi A.,Institute Pasteur Of Tunis | Namouchi A.,Institute Pasteur Paris | Karboul A.,Institute Pasteur Of Tunis | Fabre M.,Laboratoire Of Biologie Clinique | And 2 more authors.
PLoS ONE | Year: 2013

Background:PE and PE_PGRS are two mycobateria-restricted multigene families encoding membrane associated and secreted proteins that have expanded mainly in the pathogenic species, notably the Mycobacterium tuberculosis complex (MTBC). Several lines of evidence attribute to PE and PE_PGRS genes critical roles in mycobacterial pathogenicity. To get more insight into the nature of these genes, we sought to address their evolutionary trajectories in the group of smooth tubercle bacilli (STB), the putative ancestor of the clonal MTBC.Methodology/Principal Findings:By focussing on six polymorphic STB PE/PE_PGRS genes, we demonstrate significant incongruence among single gene genealogies and detect strong signals of recombination using various approaches. Coalescent-based estimation of population recombination and mutation rates (ρ and θ, respectively) indicates that the two mechanisms are of roughly equal importance in generating diversity (ρ/θ = 1.457), a finding in a marked contrast to house keeping genes (HKG) whose evolution is chiefly brought about by mutation (ρ/θ = 0.012). In comparison to HKG, we found 15 times higher mean rate of nonsynonymous substitutions, with strong evidence of positive selection acting on PE_PGRS62 (dN/dS = 1.42), a gene that has previously been shown to be essential for mycobacterial survival in macrophages and granulomas. Imprint of positive selection operating on specific amino acid residues or along branches of PE_PGRS62 phylogenetic tree was further demonstrated using maximum likelihood- and covarion-based approaches, respectively. Strikingly, PE_PGR62 proved highly conserved in present-day MTBC strains.Conclusions/Significance:Overall the data indicate that, in STB, PE/PE_PGRS genes have undergone a strong diversification process that is speeded up by recombination, with evidence of positive selection. The finding that positive selection involved an essential PE_PGRS gene whose sequence appears to be driven to fixation in present-day MTBC strains lends further support to the critical role of PE/PE_PGRS genes in the evolution of mycobacterial pathogenicity. © 2013 Namouchi et al.


PubMed | Laboratoire Of Biologie Clinique and Center Hospitalier University Purpan Toulouse
Type: Journal Article | Journal: Clinical case reports | Year: 2015

We report on a phenotypically normal 41-year-old azoospermic man with a 45 chromosomes karyotype including one normal chromosome 21, one normal chromosome 22, and a der(22)ins(22;21). Array CGH showed a 1.8Mb terminal deletion of bands 21pter to 21q21.1 and a 341kb terminal deletion on band 21q22.3.


PubMed | Cellule dInspection dHygiene, Public Health England, Laboratoire Of Biologie Clinique and Vrije Universiteit Brussel
Type: Journal Article | Journal: New microbes and new infections | Year: 2014

Corynebacterium diphtheriae and Corynebacterium ulcerans are rarely isolated from clinical samples in Belgium. A case of toxigenic C.ulcerans in a woman is described, which confirms that this pathogen is still present. During investigation of the patients cats, only a non-toxigenic toxin-bearing C.diphtheriae strain was detected.


PubMed | University of Namur, Catholic University of Louvain, Laboratoire Of Biologie Clinique and Groupe hospitalier Cochin Broca Hotel Dieu
Type: Journal Article | Journal: Annales de biologie clinique | Year: 2015

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulators level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

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