Isabelle Touitou

Tehran University of Medical Sciences, Teheran, Tehrān, Iran

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Publications (123)555.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult onset Still's disease (AOSD) is a rare inflammatory disorder characterized by hectic spiking fever, evanescent rash and joint involvement. Prognosis is highly variable upon disease course and specific involvements, ranging from benign and limited outcome to chronic destructive polyarthritis and/or life-threatening events in case of visceral complications or reactive hemophagocytic lymphohistiocytosis (RHL). AOSD remains a debatable entity at the frontiers of autoimmune diseases and autoinflammatory disorders. The pivotal role of macrophage cell activation leading to a typical Th1 cytokine storm is now well established in AOSD, and confirmed by the benefits using treatments targeting TNF-α, IL-1β or IL-6 in refractory patients. However, it remains difficult to determine predictive factors of outcome and to draw guidelines for patient management. Herein, reviewing literature and relying on our experience in a series of 8 refractory AOSD patients, we question nosology and postulate that different cytokine patterns could underlie contrasting clinical expressions, as well as responses to targeted therapies. We therefore propose to dichotomize AOSD according to its clinical presentation. On the one hand, ‘systemic AOSD’ patients, exhibiting the highest inflammation process driven by excessive IL-18, IL-1β and IL-6 production, would be at risk of life-threatening complications (such as multivisceral involvements and RHL), and would preferentially respond to IL-1β and IL-6 antagonists. On the other hand, ‘rheumatic AOSD’ patients, exhibiting pre-eminence of joint involvement driven by IL-8 and IFN-γ production, would be at risk of articular destructions, and would preferentially respond to TNF-α blockers.
    Autoimmunity Reviews 11/2014; · 7.98 Impact Factor
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    ABSTRACT: We report a case of discordant phenotypic sex in monozygotic twins mosaic 47,XXY/46,XX: monozygotic heterokaryotypic twins. The twins presented with cognitive and comprehension delay, behavioural and language disorders, all symptoms frequently reported in Klinefelter syndrome. Molecular zygosity analysis with several markers confirmed that the twins are in effect monozygotic (MZ). Array comparative genomic hybridization found no evidence for the implication of copy number variation in the phenotypes. Ultrasound scans of the reproductive organs revealed no abnormalities. Endocrine tests showed a low testosterone level in Twin 1 (male phenotype) and a low gonadotrophin level in Twin 2 (female phenotype) which, combined with the results from ultrasound examination, provided useful information for potentially predicting the future fertility potential of the twins. Blood karyotypes revealed the presence of a normal 46,XX cell line and an aneuploïd 47,XXY cell line in both patients. Examination of the chromosome constitutions of various tissues such as blood, buccal smear and urinary sediment not surprisingly showed different proportions for the 46,XX and 47,XXY cell lines, which most likely explains the discordant phenotypic sex and mild Klinefelter features. The most plausible underlying biological mechanism is a post-zygotic loss of the Y chromosome in an initially 47,XXY zygote. This would result in an embryo with both 46,XX and 47,XXY cells lines which could subsequently divide into two monozygotic embryos through a twinning process. The two cell lines would then be distributed differently between tissues which could result in phenotypic discordances in the twins. These observations emphasize the importance of regular paediatric evaluations to determine the optimal timing for fertility preservation measures and to detect new Klinefelter features which could appear throughout childhood in the two subjects.
    Human reproduction (Oxford, England). 10/2014;
  • Revue du Rhumatisme 07/2014;
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    ABSTRACT: Objectives. The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries.Methods. We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes.Results. Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever.Conclusion. We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.
    Rheumatology (Oxford, England) 02/2014; · 4.24 Impact Factor
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    ABSTRACT: Objectives Rheumatoid arthritis is a complex multifactorial disease and response to treatment varies widely from person to another. The aim of our study was to evaluate the association between various genetic biomarkers and response to anti-TNFα. Methods 59 patients with rheumatoid arthritis treated with anti-TNFα were included retrospectively and 10 candidate genes (13 SNPs and one VNTR) were analyzed: IL1RA, IL10, LTA, TGFB1, TNFα, TNF receptor II, TRAF1-C5, STAT4, TNFAIP3 and PTPN22. Clinical response was determined by the investigator assessment after 6 months of treatment. Fisher exact test was performed to analyze the impact of polymorphisms on the response to treatment. Results No significant association was found between the 14 polymorphisms and response to anti-TNFα. Among the subset of patients seronegative for ACPA (15 patients), T/T genotype for SNP TNFR II codon 196 was significantly associated with a good response to anti-TNFα (p=0.017). Moreover, in these patients, the combination of this SNP with others SNPs IL10-1087 and LTA+720 were predictive of response to anti-TNFα (respectively p=0.017 and p=0.022). Conclusion Although these findings have to be confirmed in a larger cohort, SNPs TNFRII codon 196, IL10-1087 and LTA+720 are associated with response to anti-TNFα in patients without ACPA. These SNPs could become interesting biomarkers to guide the use of anti-TNFα in rheumatoid arthritis.
    Joint, bone, spine: revue du rhumatisme 01/2014; · 2.25 Impact Factor
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    ABSTRACT: Although biologic therapies have changed the course of rheumatoid arthritis (RA), today's major challenge remains to identify biomarkers to target treatments to selected patient groups. Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA. Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab. Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors. The increase was however also found in patients with other forms of chronic inflammatory arthritis. Importantly, high serum levels of miR-125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P = 0.002). This predictive value was not limited to RA as it was also found in patients with B lymphomas. Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment.
    Mediators of Inflammation 01/2014; 2014:342524. · 3.88 Impact Factor
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    ABSTRACT: Dysspondyloenchondromatosis is a rare form of generalized enchondromatosis associated with spinal involvement. This skeletal dysplasia is characterized by multiple enchondromas present in vertebrae as well as in metaphyseal and diaphyseal parts of the long tubular bones, post-natal short stature, and early development of kyphoscoliosis. A novel heterozygous missense mutation in COL2A1 was recently identified in a patient with dysspondyloenchondromatosis. This suggests that dysspondyloenchondromatosis might expand the already broad spectrum of type II collagenopathies. Here, we report on a young girl with features of dysspondyloenchondromatosis, specifically short stature, thoracoscoliosis, and generalized enchondromas lesions. Sanger sequencing failed to detect a mutation in COL2A1. We therefore suggest that dysspondyloenchondromatosis is a genetically heterogeneous condition. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 12/2013; · 2.30 Impact Factor
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    ABSTRACT: A 15-month-old boy, born to Iranian consanguineous parents presented with intermittent neutropenia interspersed with episodes of fever and leukocytosis since early infancy. No ELA2 mutations were found and the bone marrow study was normal. At age 4 years he progressed to more typical attacks of periodic attacks of fever, abdominal pain, oral aphthous ulcers, cutaneous rash and leukocytosis. The clinical and laboratory features were compatible with the mild form of mevalonate kinase deficiency, usually named "Hyper-IgD and periodic fever syndrome" (HIDS). Genomic sequencing of the mevalonate kinase (MVK) gene revealed homozygous missense mutation (p.Val377Ile). On demand dexamethasone resulted in a rapid amelioration of febrile episodes. The presentation of intermittent neutropenia has not been reported in HIDS and deserves more attention in large patient cohorts.
    Journal of Clinical Immunology 11/2013; · 3.38 Impact Factor
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    ABSTRACT: Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient's illness. This is an essential step for the effective and targeted management of an orphan disease.
    Orphanet Journal of Rare Diseases 10/2013; 8(1):162. · 4.32 Impact Factor
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    ABSTRACT: To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.
    Annals of the Rheumatic Diseases 08/2013; · 9.11 Impact Factor
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    ABSTRACT: AIM: Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues-e.g.: colchicine dosage adjustment, maximum dosage of colchicine in children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings-have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. METHODS: A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. RESULTS: A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2mg in children; 3mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. CONCLUSION: This is a first attempt to resolve practical questions in the daily management of FMF patients.
    Seminars in arthritis and rheumatism 06/2013; · 4.72 Impact Factor
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    ABSTRACT: Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C.European Journal of Human Genetics advance online publication, 15 May 2013; doi:10.1038/ejhg.2013.113.
    European journal of human genetics: EJHG 05/2013; · 3.56 Impact Factor
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    ABSTRACT: BACKGROUND: Mutations in the TNFRSF1A gene encoding the tumour necrosis factor α cell surface receptor, TNFR1, cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases. OBJECTIVES: To describe a new exon 2-spliced transcript-TNFR1-d2-and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of TNFRSF1A and TRAPS phenotype. METHODS: Expression of TNFRSF1A transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS. RESULTS: TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570-rs767455-rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570-rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p<10(-4)) and TRAPS-like patients with this genotype experienced less fever. CONCLUSIONS: Our study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.
    Annals of the rheumatic diseases 03/2013; · 8.11 Impact Factor
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    ABSTRACT: Contexte La maladie de Behçet (MB) et la maladie de Kimura (MK) sont deux maladies inflammatoires fréquentes au Japon mais rares en Israël. Récemment, nous avons observé une famille au sein de laquelle trois membres de la fratrie étaient atteints d’une MB et un de leur frère avait une MK. Cette association familiale soulève la question d’un facteur génétique prédisposant commun à ces deux maladies. Objectif L’objectif de cette étude a été de décrire cette famille et de rechercher un allèle prédisposant commun à la MB et à la MK, au sein du gène de l’IL-10 dans la mesure où plusieurs polymorphismes mononucléotidiques (SNP) de ce gène sont connus pour être associés à la MB. Méthodes Trois membres de la fratrie atteints de MB et un de leur frère atteint de MK ont fait l’objet d’un examen clinique. L’ADN génomique a été préparé à partir d’échantillons sanguins prélevés chez les neuf membres de la famille. L’ADN a été génotypé pour les variations de séquences de six SNP sur le gène de l’IL-10. Conclusions Les SNP du gène de l’IL-10, connus comme facteurs de susceptibilité pour la MB, n’étaient pas associés à la MB dans notre famille. La question d’une susceptibilité génétique commune à la MK et à la MB nécessite de nouvelles études.
    Revue du Rhumatisme 03/2013; 80(2):157–160.
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    ABSTRACT: Background. Venous malformations (VM) result from an error in vascular morphogenesis. The first gene suspected in their development is the TEK gene (tyrosine kinase, endothelial). Mutations of this gene have been identified in several Belgian families with a dominant form of the disease. Therefore, we investigated whether mutations in this TEK gene could explain the MV development in patients of families from Tlemcen region (north-western Algeria). Methods. Genomic DNA was extracted from leucocytes of ten patients. The search for mutations in all the 23 exons and in the 5' and 3' intronic sequences flanking the TEK gene was performed using PCR amplification and direct sequencing of amplified genomic DNA. Additionally, a search for somatic mutations of the gene TEK was performed on a biopsy of the venous malformation from one of the ten eligible patients. Results. The sequencing of the 23 exons of the TEK gene revealed neither germinal mutation in our ten patients nor somatic mutation in the tissue of the biopsy. Conclusion. The absence of mutation in the TEK gene in the population studied suggests that the TEK gene is not necessarily involved in the onset of VM; its association with these malformations may differ from one population to another.
    Genetics research international. 01/2013; 2013:784789.
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    ABSTRACT: Objective: We have conducted the first study of the association of interleukin (IL)-10, tumor necrosis factor alpha (TNF-α), and IL23R-IL12RB2 region single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in Western Algeria. Methods: A total of 51 BD patients and 96 unrelated controls from West region of Algeria were genotyped by direct sequencing for 11 SNPs including 2 SNPs from the IL10 promoter [c.-819T > C (rs1800871), c.-592A > C (rs1800872)], 6 SNPs from the TNF-α promoter [c.-1211T > C (rs1799964), c.-1043C > A (rs1800630), c.-1037C > T (rs1799724), c.-556G > A (rs1800750), c.-488G > A (rs1800629), and c.-418G > A (rs361525)], and 3 SNPs from the IL23R-IL12RB2 region [g.67747415A > C (rs12119179), g.67740092G > A (rs11209032), and g.67760140T > C (rs924080)]. Results: The minor alleles c.-819T and c.-592A were significantly associated with BD [odds ratio (OR) = 2.18; 95% confidence interval (CI) 1.28-3.73, p = 0.003]; whereas, there was weaker association between TNF-α promoter SNPs or IL23R-IL12RB2 region and disease risk. Conclusion: Unlike the TNF-α and the IL23R-IL12RB2 region SNPs, the two IL10 SNPs were strongly associated with BD. The -819T, and -592A alleles and the -819TT, -819CT, and -592AA and -592CA genotypes seem to be highly involved in the risk of developing of BD in the population of Western Algeria.
    Frontiers in Immunology 01/2013; 4:342.
  • Annals of the rheumatic diseases. 01/2013;
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    ABSTRACT: Abstract To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48-60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.
    European Journal of HumanGenetics 12/2012; · 4.32 Impact Factor
  • Eldad Ben-Chetrit, Isabelle Touitou
    Clinical and experimental rheumatology 08/2012; · 2.66 Impact Factor
  • Isabelle Touitou
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    ABSTRACT: The title of this section, "New genetic interpretation of old diseases," perfectly reflects the unique history of our understanding of autoinflammatory diseases (AIDs). Indeed, the main clinical feature of most AIDs is the recurrent fever, a symptom that has been extensively documented for centuries. However, the first clear description of a patient suffering from the AID prototype, familial Mediterranean fever (FMF), has only been reported in 1908, although dating studies have shown that ancestral mutations appeared in biblical times. FMF and 11 other AID genes were identified between 1997 and 2011. The patient's care has dramatically benefited from the elucidation of the molecular defect underlying similar diseases of the innate immune system. However, accumulation of present and future sequence data let us anticipate that interpretation of genetic diagnosis will be increasingly difficult.
    Autoimmunity reviews 08/2012; 12(1):5-9. · 6.37 Impact Factor

Publication Stats

2k Citations
555.65 Total Impact Points

Institutions

  • 2013
    • Tehran University of Medical Sciences
      • Children's Medical Center Hospital
      Teheran, Tehrān, Iran
    • Abou Bakr Belkaid University of Tlemcen
      • Laboratoire de Biologie Moléculaires Appliquée et d’Immunologie
      Tlemsen, Tlemcen, Algeria
  • 2011–2013
    • Université de Montpellier 1
      • Faculté de Médecine
      Montpelhièr, Languedoc-Roussillon, France
  • 2012
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2009–2012
    • Hebrew University of Jerusalem
      • Faculty of Medicine
      Jerusalem, Jerusalem District, Israel
  • 2009–2011
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 2008–2009
    • Institut de Génétique Humaine
      Montpelhièr, Languedoc-Roussillon, France
    • Hadassah Medical Center
      • Department of Medicine
      Jerusalem, Jerusalem District, Israel
    • University Medical Center Utrecht
      • Department of Medical Genetics
      Utrecht, Provincie Utrecht, Netherlands
  • 2007–2009
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2000–2009
    • French National Centre for Scientific Research
      • Laboratoire Statistique et Génome
      Lutetia Parisorum, Île-de-France, France
  • 1997–2004
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France