Publications (11)96 Total impact
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Article: Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech.
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ABSTRACT: BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.Journal of Medical Genetics 06/2010; 47(6):377-84. · 6.36 Impact Factor -
Article: A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
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ABSTRACT: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.Nature 02/2010; 463(7281):671-5. · 36.28 Impact Factor -
Article: A new highly-penetrant form of obesity due to microdeletions on chromosome 16p11.2
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ABSTRACT: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.Nature 01/2010; 463:671-675. · 36.28 Impact Factor -
Article: Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders.
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ABSTRACT: Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11-q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling. 29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2-19 clones). No recurrent abnormality was identified. These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.Journal of Medical Genetics 12/2006; 43(11):843-9. · 6.36 Impact Factor -
Article: Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations.
Journal of Medical Genetics 10/2003; 40(9):690-6. · 6.36 Impact Factor -
Article: How to grow cubic GaN with low hexagonal phase content on (001) SiC by molecular beam epitaxy
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ABSTRACT: Molecular beam epitaxy (MBE) of cubic GaN on SiC films deposited by chemical vapor deposition on Si has been investigated by reflection high-energy electron diffraction, x-ray diffraction, photoluminescence, and micro-Raman spectroscopy. The wurtzite/zinc-blende ratio, indicative of the material quality, has been found to depend on both the initial substrate roughness and the N/metal ratio impinging on the surface. The results were consistently analyzed by assuming that the MBE growth of cubic GaN is mainly governed by the impinging active N flux, which directly determines the mean-free path of Ga adatoms. © 1998 American Institute of Physics.Journal of Applied Physics 08/1998; 84(4):2295-2300. · 2.17 Impact Factor -
Article: Estimation of a non-centrality parameter under Stein-type-like losses
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ABSTRACT: The estimation of the non-centrality parameter of a chi-squared distribution, although simple to state, leads to difficulties, both for frequentist and Bayesian inferences. We propose in this paper a family of admissible improper Bayes estimators and study the minimax behavior of these estimators under Stein loss and its symmetric version. Although no formal minimaxity result can be stated, we show through comparison with a family of natural estimators that the (restricted) minimax estimator deduced from this study is quite acceptable.Journal of Statistical Planning and Inference. 02/1996; -
Article: A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Nature. 463(7281):671-5. -
Article: Analyse coût-efficacité des stratégies de prise en charge des patients schizophrènes : place d’un antipsychotique atypique sous forme injectable à libération prolongée
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ABSTRACT: Schizophrenia is a disease affecting the young adults and amounts to approximately 300 000 people in France (12). The French public psychiatric sector takes care of approximately 150 000 adults schizophrenics : 50 % benefit from ambulatory care, 50 % are in partial or full-time hospitalization care. Schizophrenia represents the first diagnosis that psychiatric sectors take in charge (4). The costs associated with schizophrenia, mainly hospital costs, are important and were estimated at 2 % of the total medical costs in France (5). In the French social welfare system, the social costs (pensions, allowances, managements of custody or guardianship by social workers) are also to be taken into account : it amounts to a third of the global direct cost. Schizophrenia also generates indirect costs (losses of productivity and premature deaths) which would be at least equal, or even more important, than direct medical costs (11, 19). The non-compliance to the antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the lack of compliance to the treatment, estimated at 20 to 40 % (14), is a major handicap for schizophrenic patient stabilization. The poor level of compliance is due to many various causes : adverse effects that are considered unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive phases of the disease, lack of social support, complexity of the prescription, relapse itself (10). Compliance is thus influenced by the patient's clinical features, local provision of health care and the specific nature of the drug (adverse effects, pharmaceutical formulation). The atypical antipsychotics present fewer extrapyramidal side effects and reduce the cognitive deficits associated with the disease, which results in improved compliance. Long-acting injectable antipsychotics allow a better therapeutic compliance and thus better efficacy of the treatment. Several studies have shown a significant improvement in compliance related to the pharmaceutical formulation of antipsychotics. Hospitalization and relapse risks are lower in compliant than in non-compliant patients.ObjectivesThe main objective of this pharmacoeconomic analysis is to evaluate the impact in terms of medical benefits and costs of the following strategies : 1. Risperidone long-acting injection : first long-acting injectable atypical antipsychotic ; 2. Haloperidol depot : long-acting injectable conventional neuroleptic ; 3. Olanzapine : atypical antipsychotic available commercially in oral formulation.MethodsThe target population defined for the study are young schizophrenic patients treated for at least 1 year and whose disorder has not been diagnosed for longer than 5 years. The time horizon is 2 years. A costeffectiveness analysis is performed. The perspective adopted is the French Health System. The main hypothesis of the model is that an increase in compliance linked to the use of long-acting injectable formulation could lead to an increased efficacy and a modification of the cost-effectiveness ratio. A decision tree was built. Six periods of follow-up are identified with a duration of 4-months per period. The tree contains 3 principal arms, each one corresponding to a specific treatment : risperidone LA injection, haloperidol decanoate and olanzapine. For each arm, at the chance node, two health states are identified : either the patient responds favourably to the treatment or does not respond favourably and requires a switch to another drug treatment. After a period of response, the patient can either remain in the same state or experiences a clinical deterioration. If the patient presents a clinical deterioration, he can either go back to a positive response state after a period of intensive follow-up or remain in an insufficient response state ; in this case, a change of antipsychotic treatment is necessary. In the model, a patient should receive four different treatments before a long-term hospitalization takes put in place. According to the market authorization labelling, clozapine is proposed only as a 2nd or 3rd line therapeutic option, so when at least one or two successive neuroleptics have failed. The efficacy data used in the model are provided by clinical research recently published. These studies estimate the efficacy of oral risperidone, LA risperidone, olanzapine, and treatment by haloperidol. When available data in the literature were insufficient, the opinion of experts was sought. The effectiveness criteria is the rate of patients treated successfully: patients responding to the initial treatment with the possibility of experiencing one or two episodes of clinical deterioration but without requiring a switch to another drug during 2 years of follow-up. The base case is as follows : efficacy for oral risperidone is used for the LA risperidone strategy, increased by 10 % within the first 4 months of follow-up ; efficacy for oral haloperidol is used for haloperidol depot, increased by 5 % within the first 4 months of follow-up ; for olanzapine, observed data in clinical trials were applied. The hypotheses for long acting forms are rather conservative because the increase of efficacy which can be expected for the long-acting injectable formulations varies between 5 % to more than 30 % according to the literature data. The analysis of sensibility includes three scenarios : scenario 1 : for LA risperidone, 5 % of patients treated successfully improvement in regard to oral risperidone instead of 10 % in the base case ; scenario 2 : for haloperidol depot, 10 % of patients treated successfully improvement in regard of oral haloperidol instead of 5 % in the base case ; scenario 3 : the results of an open trial conducted within the framework of the LA risperidone license are used, leading to an increase of up to 13,3 % of the rate of successfully treated patients, compared to oral risperidone literature data. As for the side effects, only extrapyramidal symptoms were considered. Other side effects are described in the literature such as the obesity or the occurrence of a diabetes ; these effects were not taken into account in the model, their impact on the coverage of schizophrenic patients and on resources utilisation being poorly known. Only direct medical costs were considered in the pharmaco-economic analysis. Two types of costs were identified : hospital costs and community care costs. The stays in overnight hospitalisation and day hospitalisation were derived from the Disease Related Groups (DRG) and valued from the data of the National Cost Study (Étude Nationale de Coûts ; 1999). The DRGs corresponding to the diagnosis of schizophrenia are the DRG 627 (complete hospitalization) and DRG 819 (day hospitalisation). Ambulatory care : procedures and visits, were valued in euros in reference with the tariffs for reimbursement issued in the Naming General of the Professional Acts (NGAP) and published by the French National Health Insurance (Year 2001). Medication consumption was quantified by using the daily dosage specified in the the MAA and the French prescription database IMS-Dorema. The cost of medicines was valued from tariffs 2001 (SEMPEX). LA risperidone price being not fixed to date, the reserved hypothesis is a 141,62 O retail price. As schizophrenia is listed among the diseases reimbursed at a 100 % rate by the Health insurance, out of pocket expenses by patient are not considered in the analysis. The cost for the extrapyramidal effects was attributed to all the strategies. This cost was calculated according to the rates of extrapyramidal effects occurrence collected in the literature. Globally, in the published studies, the incidence of the side effects for the patients treated by olanzapine or risperidone is similar. It was thus decided by the experts to use the same rate of occurrence for extrapyramidal effects for olanzapine and risperidone (20 %). This rate is 40 % for haloperidol decanoate, 10 % for oral clozapine. For the cost estimation, the expenses for treating a schizophrenic patient for two years were taken into account.ResultsThe results show that in two years, LA risperidone is more effective than the two other antipsychotics. After 2 years, the rate of patients treated successfully is 82,7 % for LA risperidone, 74,8 % for olanzapine and 57,3 % for haloperidol depot. The 2 year-cost per patient treated by LA risperidone is 14 055 O. This cost is 14 351 O and 17 203 O respectively for the strategies olanzapine and haloperidol depot. The cost-efficacy ratios per patient successfully treated are 16 995 O for the strategy LA risperidone, 19 186 O for olanzapine and 30 023 O for haloperidol depot. LA risperidone is a dominant strategy compared with both olanzapine and haloperidol depot. Scenario 1 shows that LA risperidone strategy remains the most effective. Indeed, this strategy allows a response increase of 3,5 % regarding olanzapine strategy and of 21 % regarding haloperidol depot strategy. Under the hypothesis tested in scenario 1, LA risperidone is a partial dominant strategy against olanzapine and a total dominant strategy against haloperidol depot. In scenario 2, as efficacy is improved for haloperidol decanoate (61,10 %), a decrease of 1 763 O in the cost per patient treated is observed for this strategy. Cost per patient treated successfully and efficacy for LA risperidone and olanzapine are the same than in the base case. LA risperidone is a total dominant strategy against olanzapine and haloperidol decanoate. In scenario 3, the rate of patients treated successfully at 2 years is 88,6 % for LA risperidone with a cost per patient of 12 347 O. LA risperidone is dominant against olanzapine and haloperidol depot.Discussion and ConclusionThe schizophrenia is a relatively frequent disease. In France, every year, the adult care public sector welcomes approximately 150 000 patients affected by schizophrenia, among whom most are going to require a follow-up for many years. According to the French Psychiatric Federation, continuous regimens of moderate doses entail a diminished relapse risk, less re-hospitalisations, and maybe a diminished tardive dyskinesia risk ; they favour better compliance to the treatment which is probably linked to a better alliance between the patient and his physician. Improved compliance entailing an improved state of health is a plausible hypothesis which has, indeed, already been demonstrated. The benefit obtained thanks to improved compliance may go beyond purely medical aspects and entail a social benefit, which is at present very difficult to quantify. In view of the serious nature of the disorder and the frequent incidence of schizophrenia, there are not that many pharmacoeconomics published studies. The cost of the disorder has been little studied and the outcomes of such work must be interpreted on the basis of the specific characteristics of the national health care systems. No study has been made to compare the benefits of a long-acting atypical antipsychotic with those of another atypical antipsychotic or with a depot formulation conventional neuroleptic. The results observed in the various studied scenarios show a clinical and economic superiority of LA risperidone with regard to haloperidol depot and almost always with regard to olanzapine. It can suggest that a use of long-acting risperidone in first line is desirable for a better medical and economic benefit.L'Encéphale. -
Article: Molecular cytogenetic analysis of five 2q37 deletions: refining the brachydactyly candidate region.
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ABSTRACT: Deletions of the 2q37 region are associated with a recognizable pattern of MCA/MR so-called the AHO-like syndrome. Brachydactyly is a variable but characteristic feature of this clinical entity. Here we report on five cases of cytogenetically visible de novo deletions of this 2q37 chromosome region. Using FISH, we characterized at the molecular level the breakpoints of these deletions using a set of 15 BACs, PACs and YACs. In four patients, terminal deletions of variable size ranged between 6.2 and 10 Mb. The fifth patient had an interstitial deletion with an AHO-like phenotype including brachydactyly. These findings when compared to previous observations allowed us to narrow down the brachydactyly critical region between BACs RP11-585E12 and RP11-351E10. It contains HDAC4 and STK25 candidate genes loci.European Journal of Medical Genetics 49(3):255-63. · 2.18 Impact Factor -
Article: Optical properties of cubic GaN grown on SiC/Si substrates
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ABSTRACT: The optical properties of MBE cubic GaN layers grown on SiC/Si substrates were studied by photoreflectance and photoluminescence. From 9 K PR measurements, we derive the two excitons energies at 3.268 and 3.283 eV. We evidence that the PL excitonic transition observed at 3.265 eV is a combination of both donor-bound and free excitonic recombinations. Two overlapped PL components are observed at about 3.13 and 3.15 eV. The analysis of these lines behaviour as a function of temperature and excitation power allows their attribution to the D–A and e–A recombinations. Their relative intensity strongly depends on the V/III ratio.Materials Science and Engineering: B.
