Publications (19)110.94 Total impact
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Article: [Pseudohypoaldosteronisme type I: a rare cause of failure to thrive].
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ABSTRACT: We report on a boy, born on term, presenting with a weight loss and a persistent failure to thrive after 10 days despite a normal behavior under bottle-feeding. The clinical examination was normal and biological assessment revealed hyponatremia with hyponatriuria, normal kaliemia and elevated aldosterone values, leading to type I pseudohypoaldosteronism diagnosis. Treatment with salt supplementation allowed growth improvement. The diagnosis was confirmed by the identification of a mutation in the mineralocorticoid receptor. This change was also found in several family members.Archives de Pédiatrie 03/2012; 19(5):488-92. · 0.30 Impact Factor -
Article: A GPHN point mutation leading to molybdenum cofactor deficiency.
Clinical Genetics 12/2011; 80(6):598-9. · 3.13 Impact Factor -
Article: What can we learn from old microdeletion syndromes using array-CGH screening?
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ABSTRACT: Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.Clinical Genetics 07/2011; 82(1):41-7. · 3.13 Impact Factor -
Article: Hippocampal dysgenesis and variable neuropsychiatric phenotypes in patients with Bardet-Biedl syndrome underline complex CNS impact of primary cilia.
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ABSTRACT: The Bardet-Biedl syndrome (BBS) is a rare ciliopathy clinically defined by the association of retinitis pigmentosa, polydactyly, obesity, kidney disease and cognitive impairment. The cognitive functioning, behavioral phenotype, prevalence of psychiatric diseases and memory performances of a cohort of 34 patients with BBS were evaluated and a systemic brain magnetic resonance imaging (MRI) was performed. The patients' cognitive functioning was of marked variable efficiency ranging from normal to disabling performances. Neuropsychological disorders such as slow thought process, attention difficulties and obsessive-compulsive traits were observed. Our main finding was hippocampal dysgenesis, diagnosed by MRI, found in 42.31% of the patients in this cohort. Moreover, we show that BBS proteins are expressed in the human hippocampus and in the human brain in the normal subject. Recent literature in the murine model shows that hippocampal neurogenesis, in particular in the adult mouse, requires an intact primary cilia. These results encourage us to further investigate the possible role of BBS proteins in the hippocampus and related central nervous system structures.Clinical Genetics 04/2011; 80(6):523-31. · 3.13 Impact Factor -
Article: [Prenatal diagnosis of hyperechogenic kidneys: A study of 17 cases].
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ABSTRACT: To evaluate the prenatal diagnosis and the prognostic value of ultrasound in case of fetal hyperechogenic kidneys. Seventeen prenatally diagnosed cases of hyperechogenic kidneys were retrospectively reviewed at the University Hospital of Lille from 1997 to 2008. The clinical and ultrasound data were compared to the postnatal follow-up and the long-term prognosis. The aetiologies are nine recessive polycystic kidney diseases, three dominant, two Bardet-Biedl syndromes and three cases of transient renal hyperechogenicity. No renal ultrasonographic criterion is specific of aetiology. Five pregnancies were terminated. We observed one neonatal death and 11 survivors (median follow-up: 30months) including two infants with hypertension. All oligohydramnios (n=8) were associated with poor prenatal outcomes (terminations of pregnancy, neonatal death or hypertension) compared to the other nine with normal amniotic fluid volume (nine children symptom-free). Kidneys less or equal to +4 S.D. and a normal amniotic fluid volume were associated with a good prognosis (n=7, seven symptom-free). The fetal kidneys characteristics on prenatal ultrasound fail to provide an accurate etiological diagnosis. Only congenital defects and family history adjust the aetiology. Amniotic fluid volume and fetal kidney size are the best prenatal predictors of outcome.Journal de Gynécologie Obstétrique et Biologie de la Reproduction 12/2010; 39(8):637-46. · 0.42 Impact Factor -
Article: Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and Russell- Silver syndrome.
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ABSTRACT: Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.Clinical Genetics 12/2010; 81(3):265-71. · 3.13 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: Oculo-dento-digital dysplasia: lack of genotype-phenotype correlation for GJA1 mutations and usefulness of neuro-imaging.
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ABSTRACT: Oculo-dento-digital dysplasia (ODDD) is an autosomal dominant disorder with complete penetrance and high intra- and interfamilial phenotypic variability. The key features in this syndrome are microphthalmia, enamel hypoplasia and syndactyly of the 4th-5th fingers. ODDD is caused by mutations in the connexin 43 gene (GJA1). We report here four patients from three families with GJA1 mutations, one of them diagnosed prenatally. The three mutations (c.52T > C/p.Ser18Pro, c.689_690delTA/p.Tyr230CysfsX6, c.442C > G/p.Arg148Gly) have been reported once before. Two patients had white matter hypersignal anomalies, associated in one case with mental retardation, but asymptomatic in the other one, an observation that leads us to discuss systematic neuroradiological imaging for ODDD. One case has optic atrophy, another has hypospadias. The patient carrying a truncating mutation of Cx43 did not have palmoplantar keratoderma, in contradiction with the previously suggested genotype-phenotype correlation between truncating mutation and skin involvement.European journal of medical genetics 10/2009; 53(1):19-22. · 1.57 Impact Factor -
Article: Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome.
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ABSTRACT: Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.Journal of Medical Genetics 06/2006; 43(5):e22. · 6.36 Impact Factor -
Article: [Genetics and orthopedics: genetic implications of congenital limb abnormalities].
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ABSTRACT: Limb malformations are frequent. These malformations are isolated or associated with anomalies of other developmental fields and accurate diagnostic is essential for prognosis evaluation, treatment and genetic counseling. Animal embryology and molecular biology techniques, have given us a better understanding of the processes of growth and patterning of the limb buds. The key genes that are involved in these processes have been identified and their interactions recognized. Human genetics has been able to identify, or at least localize, several genes implicated in limb development. We here review the present knowledge on these genes and their mutations responsible for limb anomalies.Revue de Chirurgie Orthopédique et Réparatrice de l Appareil Moteur 03/2006; 92(1):83-94. · 0.37 Impact Factor -
Article: Angel shaped phalangeal dysplasia, hip dysplasia, and positional teeth abnormalities are part of the brachydactyly C spectrum associated with CDMP-1 mutations.
Journal of Medical Genetics 07/2004; 41(6):e78. · 6.36 Impact Factor -
Article: Towards a suggestive facial dysmorphism in adenylosuccinate lyase deficiency?
Journal of Medical Genetics 07/2002; 39(6):440-2. · 6.36 Impact Factor -
Article: Pierre Robin sequence: a series of 117 consecutive cases.
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ABSTRACT: A series of 117 cases of Pierre Robin Sequence are classified as isolated (48%), syndromic (35%), and with associated anomalies (17%); the latter group had a poor long-term prognosis. In isolated Pierre Robin Sequence, familial cases and a high incidence of twins were noted. Among syndromic Pierre Robin Sequence, 4 syndromes represent more than 50% of the diagnoses.Journal of Pediatrics 11/2001; 139(4):588-90. · 4.11 Impact Factor -
Article: IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign
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ABSTRACT: Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.Molecular syndromology 08/1970; 1(2):67-74. -
Article: Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence
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ABSTRACT: Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.Nat Genet. 41(3):359-64. -
Article: A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Nature. 463(7281):671-5. -
Article: Expanded mutational spectrum in Cohen syndrome, tissue expression, and transcript variants of COH1
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ABSTRACT: Cohen syndrome is characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in COH1 (VPS13B) have been found in patients with Cohen syndrome from diverse ethnic origins. We have carried out mutation analysis in twelve novel patients with Cohen syndrome from nine families. In this series, we have identified 13 different mutations in COH1, twelve of these are novel including six frameshift mutations, four nonsense mutations, two splice site mutations, and a one-codon deletion. Since different transcripts of COH1 have been reported previously, we have analysed the expression patterns of COH1 splice variants. The transcript variant NM_152564 including exon 28b showed ubiquitous expression in all examined human tissues. In contrast, human brain and retina showed differential splicing of exon 28 (NM_017890). Moreover, analysis of mouse tissues revealed ubiquitous expression of Coh1 homologous to human NM_152564 in all examined tissues but no prevalent alternative splicing.Hum Mutat. 30(2):E404-20. -
Article: Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome
[show abstract] [hide abstract]
ABSTRACT: Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.J Med Genet. 43(5):e22.
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Institutions
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2011
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Centre Hospitalier Universitaire de Dijon
- Cytogenetics Laboratory
Dijon, Bourgogne, France
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