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PubMed | KLES Prabhakar Kore Hospital, St. Mary's University, Uppsala University, Laboratoire Of Genetique Medicale and FRIGEs Institute of Human Genetics
Type: | Journal: Clinical genetics | Year: 2016

Duplications at 2q24.3 encompassing the voltage-gated sodium channel gene cluster are associated with early onset epilepsy. All cases described in the literature have presented in addition with different degrees of intellectual disability, and have involved neighbouring genes in addition to the sodium channel gene cluster. Here we report eight new cases with overlapping duplications at 2q24 ranging from 0.05Mb to 7.63Mb in size. Taken together with the previously reported cases, our study suggests that having an extra copy of SCN2A has an effect on epilepsy pathogenesis, causing benign familial infantile seizures which eventually disappear at the age of one to two years.. However, the number of copies of SCN2A does not appear to have an effect on cognitive outcome.


PubMed | Service de Pediatrie 1, Laboratoire Of Cytologie, Service de Soins de Suite et de Reeducation Pediatrique, Laboratoire Of Genetique Medicale and 11 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.


PubMed | Nancy University Hospital Center, Service de Genetique Clinique, Laboratoire Of Cytogenetique Constitutionnelle Et Prenatale, Lyon University Hospital Center and 21 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228kb to 11.7Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n=20), reduced volume of the white matter (WM) (n=12), ventricular dilatation (n=9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n=6), and vermis hypoplasia (n=5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.


Mouawia H.,University of Paris Descartes | Mouawia H.,Lebanese University | Saker A.,University of Paris Descartes | Saker A.,Damascus University | And 9 more authors.
Reproductive BioMedicine Online | Year: 2012

This study sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of cystic fibrosis (CF) or spinal muscular atrophy (SMA) can be achieved through analysis of circulating fetal trophoblastic cells (CFTC). The kinetics of CFTC circulation were also studied. CFTC were isolated by isolation by size of epithelial tumour/trophoblastic cells at 9-11 weeks of gestation, before chorionic villus sampling (CVS), from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n = 32) or SMA (n = 31). Collected cells were laser-microdissected, short tandem repeat-genotyped to determine fetal origin and blindly assessed for mutation analysis. CFTC were independently analysed weekly (4-12 weeks of gestation) in 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity (95% CI 76.8-100%) and specificity (95% CI 92.7-100%) in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. We sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of two rare genetic diseases - cystic fibrosis (CF) and spinal muscular atrophy (SMA) - can be achieved through analysis of circulating fetal trophoblastic cells (CFTC) in blood of pregnant women. We also studied the time of appearance and circulation of CFTC in maternal blood. CFTC were isolated from maternal blood by isolation by size of epithelial tumour/trophoblastic cells (ISET; an approach for cell isolation from blood) at 9-11 weeks of gestation before chorionic villus sampling (CVS) from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n = 32) or SMA (n = 31). Collected cells were analysed by genetic test to determine fetal origin and blindly assessed for mutation analysis. We independently analysed CFTC in maternal blood samples taken weekly (4-12 weeks of gestation) from 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity and specificity in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. © 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Koob M.,Service de Radiologie 2 | Doray B.,Laboratoire Of Genetique Medicale | Fradin M.,Laboratoire Of Genetique Medicale | Astruc D.,Service de Neonatologie | Dietemann J.-L.,Service de Radiologie 2
Pediatric Radiology | Year: 2011

We describe ante- and postnatal imaging of a 1-year-old otherwise healthy girl with Raine syndrome. She presented with neonatal respiratory distress related to a pyriform aperture stenosis, which was diagnosed on CT. Signs of chondrodysplasia punctata, sagittal vertebral clefting and intervertebral disc and renal calcifications were also found on imaging. This new case confirms that Raine syndrome is not always lethal. The overlapping imaging signs with chondrodysplasia punctata and the disseminated calcifications give new insights into its pathophysiology. © 2011 Springer-Verlag.


Rossignol S.,French Institute of Health and Medical Research | Netchine I.,French Institute of Health and Medical Research | Faivre L.,University of Burgundy | Weill J.,Service dEndocrinologie Pediatrique | And 7 more authors.
Human Mutation | Year: 2011

The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS. © 2011 Wiley-Liss, Inc.


Peigne M.,Service de Gynecologie Endocrinienne et Medecine de la Reproduction | Andrieux J.,Laboratoire Of Genetique Medicale | Deruelle P.,Service de Gynecologie et dObstetrique | Vuillaume I.,Laboratoire Of Biochimie Et Biologie Moleculaire | Leroy M.,Service de Gynecologie Endocrinienne et Medecine de la Reproduction
Fertility and Sterility | Year: 2011

Objective: To report a genetically proved superfecundation of quintuplets after transfer of two embryos in IVF procedure and successful completion of the pregnancy after fetal reduction. Design: Case report. Setting: Academic reproductive medicine center. Patient(s): A 31-year-old woman, gravida 0, who underwent her second IVF cycle after three IUIs. Intervention(s): After 5 years of primary infertility, three IUIs, and one IVF, the patient underwent her second IVF cycle with transfer of two fresh embryos on day 2. Main Outcome Measure(s): Development of five separate embryonic sacs. Fetal reduction to twins at 12 weeks of gestation. Successful pregnancy and delivery. Deoxyribonucleic acid analysis of the three reduced embryos, the live-born twins, and their parents. Result(s): Analysis of the seven DNA samples, because all were different, confirmed the superfecundation and disproved the zygote's division after transfer. Fetal growth restriction motivated preterm delivery by cesarean section. Both twins were in good health. Conclusion(s): Superfecundation can explain high-order multiple pregnancy and can be proved by DNA analysis. Couples must be informed because of the implications of fetal reduction for ethical issues, risks of pregnancy loss, fetal growth restriction, preterm delivery, and its consequences. © 2011 by American Society for Reproductive Medicine.


Bibolini M.J.,National University of Cordoba | Scerbo M.J.,National University of Cordoba | Scerbo M.J.,Laboratoire Of Genetique Medicale | Roth G.A.,National University of Cordoba | Monferran C.G.,National University of Cordoba
Neuroscience | Year: 2014

Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are crucially dependent on the invasion of activated autoreactive lymphocytes and blood macrophages into the central nervous system (CNS). Proinflammatory mononuclear cells and activated local microglia mediate inflammation, demyelination and axonal damage at the target organ. Previously, we observed that the administration of a hybrid between the synapsin ABC domains and the B subunit of Escherichia coli heat labile-enterotoxin (LTBABC) to rats with EAE ameliorated disease by modulating the peripheral Th1 response to myelin basic protein (MBP). In the present study, we investigated the effect of LTBABC administration on proinflammatory cell frequency in the CNS of rats with EAE. Treatment with the hybrid in the inductive phase of EAE attenuated disease severity and diminished histological inflammatory infiltrates and demyelination in the spinal cord of rats with acute EAE. Lower frequencies of infiltrating and local macrophages as well as CD4+ T cells that produce the proinflammatory cytokines interferon-gamma (IFN-γ) and interleukin (IL)-17 were found at the target organ. Concomitantly, low levels of INF-γ and IL-17 and increased levels of IL-10 were measured in cultures of CNS infiltrating cells and spinal cord tissue. An increased frequency of CD4+CD25+Foxp3 cells was observed at the disease peak and at the beginning of the recovery stage. These results provide further evidence for the immunomodulatory properties of the fusion protein LTBABC in autoimmune demyelinating disease affecting the central nervous system. © 2014 IBRO.


Petit F.,Service de Genetique Clinique | Petit F.,University of Lille Nord de France | Plessis G.,Caen University Hospital Center | Decamp M.,Laboratoire Of Genetique Medicale | And 4 more authors.
European Journal of Medical Genetics | Year: 2015

Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment. © 2014 Elsevier Masson SAS.

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