A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Dossier : préparer le CAPEPS

Sommaire du dossier Prépa CAPEPS présenté par l'équipe de l'UFRSTAPS de Liévin : 'La première épreuve écrite d'admissibilité' (O. Chovaux); 'La deuxième épreuve écrite d'admissibilité' (V. Boutin); 'Préparer l'oral 1 : de l'observation à l'argumentation' (V. Vandenberghe, N. Niedzwialowska); 'Oral 2 : un premier entretien d'embauche' (A. Lejot); 'Oral 3 danse : au secours je suis admissible' (V. Obry

Is the use of the QPC cognitive complaints questionnaire relevant for the screening strategy of HIV-Associated neurocognitive disorders?

International audienceBackground: The screening strategy for HIV-Associated Neurocognitive Disorders (HAND) is challenging. The French Expert Report recommend the use of the Cognitive Complaints Questionnaire (QPC) and the Montreal Cognitive assessment. However, the QPC has never been studied in People Living with HIV (PLWH). This study aims to determine the degree of agreement between QPC and the presence of HAND according to Frascati criteria, established by a battery of neuropsychological tests.Methods: Data from patients who performed both a QPC and a battery of neuropsychological tests over a six-month follow-up period were evaluated retrospectively.Results: A total of 121 patients were selected, with a median age of 53.1 years old. Among participants, 92.6% had an undetectable plasma viral load, 49.6% had a nadir CD4 less than 200/mm3 and 23.1% had a CDC stage C. Median CD4 cell count was 686/mm3. Prevalence of HAND was 57%, including 28.9% of Asymptomatic Neurocognitive Impairment, 24.8% of Mild Neurocognitive Disorder and 3.3% of HIV-associated Dementia. This analyze shows no agreement between QPC and HIV-associated neurocognitive disorders (kappa = -0.007).Conclusions: The QPC is not relevant in the screening for HAND. Thus, it urges to develop a specific tool to assess cognitive complaints among PLWH

Frailty in HIV infected people: a new risk factor for bone mineral density loss

International audienceObjective: The study aims to assess the association between bone mineral density (BMD) and frailty in a cohort of HIV-infected patients. Design: A cross-sectional study in an HIV outpatient unit where nearly 1000 patients are monitored. Methods: Study participants undergoing bone densitometry were proposed an evaluation of frailty using criteria of the Cardiovascular Health Study (CHS) and the Study of Osteoporotic Fractures (SOF). Frailty markers were weight-loss, self-reported exhaustion , physical activity, grip strength, chair stands, and slow gait. Patients' characteristics were collected from an electronic medical record. Associations of frailty with BMD and osteoporosis were tested using multivariate linear and logit regression models, respectively. Results: In total, 175 HIV-infected patients, 121 (69.14%) men, were analyzed. Prevalence of frailty markers, osteopenia, and osteoporosis were comparable among sexes. Despite a younger age, spinal and femoral neck BMD were lower in women (P < 0.05). Linear regression model adjusting by age, duration of HIV follow-up, BMI, smoking status, osteoarthritis, osteoporosis treatment, and the age at menopause showed a negative association of spinal and femoral BMD with frailty according to SOF criteria in women (P < 0.05). In men, SOF-defined frailty was associated with osteoporosis (odds ratio 28.79; 95% confidence interval 2.15-386.4) in a model adjusting for age, duration of HIV follow-up, CD4 þ nadir, CD4 þ T-cell count, tobacco consumption, exposure to tenofovir (TDF) and protease inhibitors. No significant associations were found between BMD and CHS-defined frailty. Conclusion: Our study shows that frailty according to SOF criteria is associated with low spinal BMD values in female and osteoporosis in male HIV-infected patients

Impact of hepatitis C virus coinfection on T-cell dynamics in long-term HIV-suppressors under combined antiretroviral therapy

International audienceObjective: The objective of this study is to evaluate the impact of hepatitis C virus (HCV) serostatus on the evolution of CD8 þ cells and CD4 þ : CD8 þ ratio in HIV-infected patients on combined antiretroviral therapy (cART) who achieve sustained undetectable viral load (HIV-pVL). Design and methods: A longitudinal study performed in an outpatient HIV-unit following 1495 HIV-infected patients. Data of patients on cART achieving undetectable HIV-pVL for at least 3 years were collected retrospectively from our medical e-database NADIS from January 1997 to April 2005, a period defined in order to select patients who were naive of hepatitis treatment. T-cell counts were assessed every 6 months from HIVsuppression over the study period. Results: Two hundred and twenty-six HIV mono-infected (group 1) and 130 HCVcoinfected patients (group 2; genotype prevalence: 42% HCV-G1, 26% HCV-G3, 11% HCV-G4 and 21% HCV-G2) fulfilled the selection criteria. cART regimens were comparable between the groups, as were CD4 þ and CD8 þ cell counts at the first undetectable HIV-pVL. After 3 years, both groups displayed similar CD4 þ cell reconstitution, although CD4 þ percentage was higher in group 1 (30.3 AE 1.1 vs. 27 AE 1.1%; P < 0.001). HIV suppression led to a significant drop of median CD8 þ cell counts in group 1 (P ¼ 0.027), but not in group 2, which displayed higher CD8 þ cell counts all through the follow-up (mean diff. ¼ 135.71 AE 26.89 cells/ml, P < 0.001). Moreover, the fraction of patients reaching CD4 þ : CD8 þ ratio ! 1 was lower in group 2 (14 vs. 27.7%; P < 0.05). Conclusion: Despite sustained HIV suppression under cART, HCV coinfection was found to hamper CD8 þ downregulation. Further studies will determine the impact of treatment with direct-acting antiviral agents on the CD8 þ pool, and the advantage of systematic HCV-targeted therapy for HIV/HCV-coinfected patients

First-line cART regimen impacts the course of CD8+ T-cell counts in HIV-infected patients that achieve sustained undetectable viral load.

International audienceThe aim of the study was to investigate the impact of first-line combined antiretroviral therapy (cART) regimen on the course of CD8 + T-cell counts in human immunodeficiency virus (HIV)-infected patients. A retrospective observational study conducted on the French DAT'AIDS Cohort of HIV-infected patients. We selected 605 patients initiating a first-line cART between 2002 and 2009, and which achieved a sustained undetectable HIV plasma viral load (pVL) for at least 12 months without cART modification. The evolution of CD8 + T-cell counts according to cART regimen was assessed. CD8 + T-cell counts were assessed in 572 patients treated with 2NRTIs+1PI/r (n= 297), 2NRTIs+1NNRTI (n= 207) and 3NRTIs (n= 68). In multivariate analysis, after 12 months of follow-up, the 3NRTIs regimen was associated with a significantly smaller decrease of CD8 + T-cell count compared with NNRTI-containing regimens (–10.2 cells/mL in 3NRTIs vs –105.1 cells/mL; P=0.02) but not compared with PI-containing regimens (10.2 vs –60.9 cells/mL; P=0.21). After 24 months, the 3NRTIs regimen was associated with a smaller decrease of CD8 + T-cell count and % compared with PI/r-and NNRTI-containing regimens (0.2 in 3NRTIs vs –9.9 with PI/r-regimens, P=0.001, and vs –11.1 with NNRTI-regimens, p < 0.0001). A focus analysis on 11 patients treated with an INSTI-containing cART regimen during the study period showed after 12 months of follow-up, a median decrease of CD8 + T-cell count of –155 [inter quartile range: –302; –22] cells/mL. Our data highlight the fact that cART regimens have differential effects on CD8 pool down regulation. Abbreviations: cART = combined antiretroviral therapy, HIV = human immunodeficiency virus, INSTI = integrase strand transfer inhibitor, NNRTI = non-nucleotide reverse transcriptase inhibitor, NRTI = nucleotide reverse transcriptase inhibitor, PI/r = Ritonavir-boosted protease inhibitor, pVL = plasma viral load