Sylvie Odent

Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud, Clamart, Île-de-France, France

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Publications (250)926.65 Total impact

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    ABSTRACT: A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated non-consanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*) and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Human Mutation
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    ABSTRACT: Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE, and are often inherited from an unaffected parent underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing (WES) and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. We report here two HPE families in which two mutations are implicated in the disease. In the first family presenting two fetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance SHH/DISP1 and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counseling.
    No preview · Article · Jan 2016 · Clinical Genetics
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    ABSTRACT: Background: 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 families.
    No preview · Article · Jan 2016 · European journal of medical genetics
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    ABSTRACT: Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to an heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: 1) intrauterine growth retardation and postnatal short stature, 2) feeding difficulties and/or gastro-oesophageal reflux, 3) microcephaly, 4) intellectual disability and 5) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and three in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for twenty cases which does not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counseling.
    No preview · Article · Dec 2015 · Clinical Genetics
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    ABSTRACT: Background: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. Methods: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. Results: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. Conclusions: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.
    Preview · Article · Dec 2015 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.European Journal of Human Genetics advance online publication, 2 December 2015; doi:10.1038/ejhg.2015.250.
    No preview · Article · Dec 2015 · European journal of human genetics: EJHG
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    ABSTRACT: Nous rapportons le cas d’un garçon de 2 ans suivi pour un retard psychomoteur, un strabisme, une asymétrie hémi-corporelle et une hypotonie axiale. Devant ces troubles du développement, une analyse chromosomique par puce à ADN (ACPA) et un caryotype sanguin ont été réalisés. L’ACPA n’a pas montré de déséquilibre alors que le caryotype a mis en évidence la présence d’un chromosome marqueur surnuméraire (SMC) dans la moitié des métaphases (mos 46,XY,+mar[9]/46,XY[11]dn). Ce SMC n’a pas pu être identifié par FISH (sondes centromériques des chromosomes X, Y, 3, 4, 8, 9, 10, 11, 12, 14/22, 15, 16, 18 et 20). Ces résultats ont motivé la réalisation d’analyses cytogénétiques conventionnelles et moléculaires sur fibroblastes cutanés. Le SMC, observé dans 6 des 24 métaphases analysées, a une taille variable et est souvent plus volumineux que celui observé sur le caryotype sanguin. L’ACPA a montré qu’il s’agit d’un dérivé du chromosome 19 (faible mosaïque). Il correspond a priori à un anneau du 19 (mos 47,XY,+r(19)(p12q13.2)[6]/46,XY[18].arr[hg19] 19p12(20,594,660-24,340,741)x2∼3,19q11q13.2 (28,272,497-41,082,079)x2-3). Cette anomalie chromosomique explique vraisemblablement le retard global des acquisitions chez le patient. Il explique aussi l’infiltration graisseuse, qui est probablement en lien avec la présence dans l’anneau du gène AKT2, responsable, en cas de mutation gain de fonction, d’un syndrome avec hypoglycémie et hémi-hypertrophie corporelle. La composition variable du SMC entre tissus d’origine différente est un phénomène rarement rapporté. La discordance des résultats obtenus par les différentes analyses réalisées sur sang et peau montre leur complémentarité pour l’identification des SMC
    No preview · Article · Dec 2015
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    ABSTRACT: Objet L’insuffisance ovarienne prématurée (IOP) est une pathologie caractérisée par une absence ou un arrêt de la fonction ovarienne normale avant l’âge de 40 ans. Elle peut se manifester par une aménorrhée ou par une ménopause précoce. Elle est caractérisée au niveau hormonal par un hypo-œstrogénisme avec augmentation de l’excrétion des hormones gonadotrophiques. Les étiologies sont très hétérogènes et les anomalies chromosomiques semblent représenter 15 à 20 % des causes rapportées. Neuf régions critiques (premature ovarian failure [POF] 1 à 9) ont été décrites dans la littérature dont les loci POF1 et POF2 localisées sur le bras long du chromosome X (Xq26-Xq28 et Xq13.3-Xq21.1, respectivement). Ces deux régions seraient porteuses de gènes impliqués dans le développement ovarien. Parmi les gènes candidats localisés au niveau de ces régions, outre FMR1 (Xq27.3), on peut retenir le gène DIAPH2 (Xq22), le gène XPNPEP2 (Xq25) et le gène ZFX (Xq22.2-Xp21.3). Méthode Des analyses cytogénétiques : caryotype en bandes RHG, analyse chromosomique par puce à ADN (ACPA) et FISH ont été réalisés chez 2 femmes présentant une IOP. Résultats La première patiente est porteuse d’une délétion terminale Xq27.2q28 d’environ 14,4 Mb, incluant POF1 dont le principal gène candidat est FMR1. La deuxième patiente est porteuse d’une duplication interstitielle Xq23.32q22.1 d’environ 8,4 Mb au niveau de POF2 avec le gène DIAPH2, et d’une délétion terminale Xq22.1q28 d’environ 53,5Mb incluant POF1. Ces deux remaniements sont localisés sur le même chromosome X et résultent d’un mécanisme d’inversion-délétion-duplication non médié par recombinaison homologue non allélique (NAHR). Discussion La présence d’une délétion Xq terminale impliquant POF1 chez ces deux patientes conforte le rôle de cette région dans la survenue d’une IOP. Par ailleurs, aucun cas d’inversion-délétion-duplication du bras long du chromosome X chez une femme présentant une IOP n’est rapporté dans la littérature. Une perte de fonction du gène DIAPH2 a quant à elle été décrite comme responsable d’IOP, cependant, le rôle d’une duplication impliquant POF2 et ce gène DIAPH2 reste à établir
    No preview · Article · Dec 2015
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    ABSTRACT: Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Since aCGH interrogates the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except 4. These 4 IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
    No preview · Article · Nov 2015 · Clinical Genetics
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    ABSTRACT: 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.
    Full-text · Article · Oct 2015 · Journal of Medical Genetics
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    ABSTRACT: SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR < 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
    No preview · Article · Oct 2015 · Clinical Genetics
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    ABSTRACT: Oto-Palato-Digital spectrum disorders (OPDSD) include OPD syndromes type 1 and 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.
    No preview · Article · Sep 2015 · Clinical Genetics
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    ABSTRACT: To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.European Journal of Human Genetics advance online publication, 23 September 2015; doi:10.1038/ejhg.2015.192.
    No preview · Article · Sep 2015 · European journal of human genetics: EJHG
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    ABSTRACT: The RASopathies constitute a family of autosomal dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering son of sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its auto-inhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the Dbl homology domain. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Human Mutation
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    ABSTRACT: Few studies have focused on reproductive health care for women with spina bifida. This subject is rarely discussed, whether in patient groups or in the medical community. However, these patients need advice and a care that is appropriate to their condition. In association with the spina bifida reference center of the University Hospital of Rennes, we have conducted a four-year retrospective, observational study. Its aim was to analyze the characteristics of the patients' gynecological care and to adapt our practice to their needs. Forty-eight patients were included. We demonstrated an increased risk of precocious puberty, labia minora hypertrophy and genital prolapse. Some specific characteristics of the reproductive health care of patients with spina bifida are interesting to know. A study on a larger series of patients is needed to further analyze the obstetric, gynecological and sexological issues of these women. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    No preview · Article · Jun 2015 · Gynécologie Obstétrique & Fertilité
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    ABSTRACT: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one were inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. Four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Human Mutation
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    ABSTRACT: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email:
    Full-text · Article · May 2015 · European Heart Journal
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    ABSTRACT: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.Genet Med advance online publication 19 March 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.29.
    No preview · Article · Mar 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
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    ABSTRACT: Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR). The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments. The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.
    No preview · Article · Mar 2015
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    ABSTRACT: Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · The American Journal of Human Genetics

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5k Citations
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  • 2015
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
    • Université Montpellier 2 Sciences et Techniques
      Montpelhièr, Languedoc-Roussillon, France
  • 2009-2015
    • Université de Rennes 1
      • Faculty of Medicine
      Roazhon, Brittany, France
  • 2001-2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1998-2014
    • Université de Rennes 2
      Roazhon, Brittany, France
  • 1988-2014
    • Centre Hospitalier Universitaire de Rennes
      • Service de génétique clinique
      Roazhon, Brittany, France
  • 2012
    • University of Tours
      Tours, Centre, France
  • 2009-2010
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
  • 2006
    • National Institutes of Health
      Maryland, United States