Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation.

International audienceChromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome

Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia

65Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.openopenPatrizia Noris; Nicole Schlegel; Catherine Klersy; Paula G. Heller; Elisa Civaschi; Nuria Pujol-Moix; Fabrizio Fabris; Remi Favier; Paolo Gresele; Véronique Latger-Cannard; Adam Cuker; Paquita Nurden; Andreas Greinacher; Marco Cattaneo; Erica De Candia; Alessandro Pecci; Marie-Françoise Hurtaud-Roux; Ana C. Glembotsky; Eduardo Muñiz-Diaz; Maria Luigia Randi; Nathalie Trillot; Loredana Bury; Thomas Lecompte; Caterina Marconi; Anna Savoia; Carlo L. Balduini; Sophie Bayart; Anne Bauters; Schéhérazade Benabdallah-Guedira; Françoise Boehlen; Jeanne-Yvonne Borg; Roberta Bottega; James Bussel; Daniela De Rocco; Emmanuel de Maistre; Michela Faleschini; Emanuela Falcinelli; Silvia Ferrari; Alina Ferster; Tiziana Fierro; Dominique Fleury; Pierre Fontana; Chloé James; Francois Lanza; Véronique Le Cam Duchez; Giuseppe Loffredo; Pamela Magini; Dominique Martin-Coignard; Fanny Menard; Sandra Mercier; Annamaria Mezzasoma; Pietro Minuz; Ilaria Nichele; Lucia D. Notarangelo; Tommaso Pippucci; Gian Marco Podda; Catherine Pouymayou; Agnes Rigouzzo; Bruno Royer; Pierre Sie; Virginie Siguret; Catherine Trichet; Alessandra Tucci; Béatrice Saposnik; Dino VeneriPatrizia, Noris; Nicole, Schlegel; Catherine, Klersy; Paula G., Heller; Elisa, Civaschi; Nuria Pujol, Moix; Fabrizio, Fabris; Remi, Favier; Paolo, Gresele; Véronique Latger, Cannard; Adam, Cuker; Paquita, Nurden; Andreas, Greinacher; Marco, Cattaneo; Erica De, Candia; Alessandro, Pecci; Marie Françoise Hurtaud, Roux; Ana C., Glembotsky; Eduardo Muñiz, Diaz; Maria Luigia, Randi; Nathalie, Trillot; Loredana, Bury; Thomas, Lecompte; Caterina, Marconi; Savoia, Anna; Carlo L., Balduini; Sophie, Bayart; Anne, Bauters; Schéhérazade Benabdallah, Guedira; Françoise, Boehlen; Jeanne Yvonne, Borg; Bottega, Roberta; James, Bussel; DE ROCCO, Daniela; Emmanuel de, Maistre; Faleschini, Michela; Emanuela, Falcinelli; Silvia, Ferrari; Alina, Ferster; Tiziana, Fierro; Dominique, Fleury; Pierre, Fontana; Chloé, James; Francois, Lanza; Véronique Le Cam, Duchez; Giuseppe, Loffredo; Pamela, Magini; Dominique Martin, Coignard; Fanny, Menard; Sandra, Mercier; Annamaria, Mezzasoma; Pietro, Minuz; Ilaria, Nichele; Lucia D., Notarangelo; Tommaso, Pippucci; Gian Marco, Podda; Catherine, Pouymayou; Agnes, Rigouzzo; Bruno, Royer; Pierre, Sie; Virginie, Siguret; Catherine, Trichet; Alessandra, Tucci; Béatrice, Saposnik; Dino, Vener

Cognitive profile in Silver-Russell syndrome: a first French study in adults.

International audienc

Cognitive and psychosocial profile in Silver-Russell syndrome: a first study in adults.

International audienc

Cognitive profile in Silver-Russell syndrome: a first French study in adults.

International audienc

Profil cognitif dans le syndrome de Silver-Russell : une première étude française chez les adultes.

International audienc

Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts

Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts

Karyotype is not dead (yet)!

International audienceBackground: While array-comparative genomic hybridization (a-CGH) and next-generation sequencing (NGS or exome) technologies have swiftly spread throughout the medical field, karyotype has gradually lost its leading role among genetic tests. Several international guidelines recommend starting with a-CGH screening then going on with exome analysis when investigating a patient with intellectual disability (ID) and no precise clinical diagnosis. A-CGH and whole exome sequencing increase etiologic diagnoses rate up to 30% in case of ID. However, physicians have to deal with the lack of qualitative information of the genome. Especially, exome and a-CGH analysis fail to detect chromosomal rearrangements because breakpoints are either located in introns or not associated with a gain or loss of genetic material. If these technologies cannot easily identify chromosomal translocations or inversions which sometimes split a gene, karyotype can. Discussion: For the 5 cases described, karyotype provided the right diagnosis for a Mendelian disease while molecular analysis remained unsuccessful. We conclude that when a Mendelian disease is strongly suggested clinically, if molecular analysis is normal, it could be very useful to carry out a karyotype in order to demonstrate a chromosomal rearrangement involving the targeted gene. If this gene is disrupted, the physician can confirm the suspected disease and give appropriate genetic counseling. Summary This article aims at keeping in mind that karyotype, this old-fashioned genetic tool, can still remain powerful and useful within some genetic issues. Even in this modern period of whole exome sequencing, young geneticists should know that karyotype remains a powerful and cheap technology, available throughout the world and can still do a lot for familie