Michel Vekemans

Publications (86)621.34 Total impact

• Article: EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.

  Christopher T Gordon, Florence Petit, Myriam Oufadem, Charles Decaestecker, Anne-Sophie Jourdain, Joris Andrieux, Valérie Malan, Jean-Luc Alessandri, Geneviève Baujat, Clarisse Baumann, [......], Ingrid Simonic, Arnold Munnich, Michel Vekemans, Nicole Porchet, Loïc de Pontual, Sabine Sarnacki, Tania Attie-Bitach, Stanislas Lyonnet, Muriel Holder-Espinasse, Jeanne Amiel
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  ABSTRACT: : Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. : We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). : These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.
  Journal of Medical Genetics 12/2012; 49(12):737-46. · 6.36 Impact Factor
• Article: Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome.

  Audrey Putoux, Sheela Nampoothiri, Nicole Laurent, Valérie Cormier-Daire, Philip L Beales, Albert Schinzel, Deborah Bartholdi, Caroline Alby, Sophie Thomas, Nadia Elkhartoufi, Amale Ichkou, Julie Litzler, Arnold Munnich, Férechté Encha-Razavi, Rajesh Kannan, Laurence Faivre, Nathalie Boddaert, Anita Rauch, Michel Vekemans, Tania Attié-Bitach
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  ABSTRACT: Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS.
  Journal of Medical Genetics 11/2012; 49(11):713-20. · 6.36 Impact Factor
• Article: Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations.

  Marine Legendre, Marie Gonzales, Géraldine Goudefroye, Frédéric Bilan, Pauline Parisot, Marie-José Perez, Maryse Bonnière, Bettina Bessières, Jelena Martinovic, Anne-Lise Delezoide, [......], Caroline Alby, Amale Ichkou, Roselyne Gesny, Alain Kitzis, Yves Ville, Stanislas Lyonnet, Ferechte Razavi, Brigitte Gilbert-Dussardier, Michel Vekemans, Tania Attié-Bitach
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  ABSTRACT: BACKGROUND: CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. METHOD: Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. RESULTS: Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation. CONCLUSIONS: Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.
  Journal of Medical Genetics 09/2012; · 6.36 Impact Factor
• Article: TCTN3 mutations cause Mohr-Majewski syndrome.

  Sophie Thomas, Marine Legendre, Sophie Saunier, Bettina Bessières, Caroline Alby, Maryse Bonnière, Annick Toutain, Laurence Loeuillet, Katarzyna Szymanska, Frédérique Jossic, [......], Christine Bole-Feysot, Patrick Nitschke, Stanislas Lyonnet, Arnold Munnich, Colin A Johnson, Férechté Encha-Razavi, Valérie Cormier-Daire, Christel Thauvin-Robinet, Michel Vekemans, Tania Attié-Bitach
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  ABSTRACT: Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.
  The American Journal of Human Genetics 08/2012; 91(2):372-8. · 10.60 Impact Factor
• Source

  Available from: Heather Corbett Etchevers

  Article: Transcriptome profiling of genes involved in neural tube closure during human embryonic development using long serial analysis of gene expression (long-SAGE).

  Deidre R Krupp, Pu-Ting Xu, Sophie Thomas, Andrew Dellinger, Heather C Etchevers, Michel Vekemans, John R Gilbert, Marcy C Speer, Allison E Ashley-Koch, Simon G Gregory
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  ABSTRACT: Neural tube defects (NTDs) are common human birth defects with a complex etiology. To develop a comprehensive knowledge of the genes expressed during normal neurulation, we established transcriptomes from human neural tube fragments during and after neurulation using long Serial Analysis of Gene Expression (long-SAGE). Rostral and caudal neural tubes were dissected from normal human embryos aged between 26 and 32 days of gestation. Tissues from the same region and Carnegie stage were pooled (n ≥ 4) and total RNA extracted to construct four long-SAGE libraries. Tags were mapped using the UniGene Homo sapiens 17 bp tag-to-gene best mapping set. Differentially expressed genes were identified by chi-square or Fisher's exact test, and validation was performed for a subset of those transcripts using in situ hybridization. In silico analyses were performed with BinGO and EXPANDER. We observed most genes to be similarly regulated in rostral and caudal regions, but expression profiles differed during and after closure. In silico analysis found similar enrichments in both regions for biologic process terms, transcription factor binding and miRNA target motifs. Twelve genes potentially expressing alternate isoforms by region or developmental stage, and the microRNAs miR-339-5p, miR-141/200a, miR-23ab, and miR-129/129-5p are among several potential candidates identified here for future research. Time appears to influence gene expression in the developing central nervous system more than location. These data provide a novel complement to traditional strategies of identifying genes associated with human NTDs and offer unique insight into the genes associated with normal human neurulation. Birth Defects Research (Part A) 94:683-692, 2012. © 2012 Wiley Periodicals, Inc.
  Birth Defects Research Part A Clinical and Molecular Teratology 07/2012; 94(9):683-92. · 2.27 Impact Factor
• Article: Apoptose et ségrégation méiotique dans les spermatozoïdes d'hommes porteurs de translocations

  Anne Le Du, Marc Lelorc'h, Nelly Frydman, Moncef Benkhalifa, Serge Romana, Michel Vekemans, René Frydman, Gérard Tachdjian
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  ABSTRACT: Les hommes porteurs d'une translocation chromosomique produisent un pourcentage significatif de spermatozoïdes avec une combinaison déséquilibrée de la translocation chromosomique. Dans le but de déterminer une corrélation entre les anomalies chromosomiques et l'apoptose dans les spermatozoïdes humains, nous avons analysé la fragmentation de l'ADN spermatique et la ségrégation méiotique chez des hommes porteurs d'une translocation Robertsonienne (13;14). L'étude a été réalisée sur des échantillons de spermatozoïdes provenant de 12 hommes porteurs d'une translocation Robertsonienne (13;14) et de 9 hommes féconds ayant un caryotype normal. La ségrégation méiotique des chromosomes 13 et 14 a été analysée par hybridationin situ fluorescente double couleur avec des sondes d'ADN spécifiques des chromosomes 13 et 14. L'apoptose dans les spermatozoïdes a été analysée par la technique TUNELin situ. L'étude de la ségrégation méiotique a montré une fréquence moyenne de 15,9% de spermatozoïdes déséquilibrés pour les chromosomes 13 et 14 chez les hommes porteurs de la translocation Robertsonienne (13;14) significativement différente de la fréquence moyenne de 1,3% observée dans la population contrôle (p=0,00016). L'étude de l'apoptose a montré un pourcentage moyen de fragmentation de l'ADN spermatique significativement plus élevé chez les hommes porteurs de translocations (34,9%) par rapport à la population contrôle (13,8%) (p=0,0036). Cette augmentation de l'apoptose a été observée dans des spermatozoïdes où il existe une augmentation des déséquilibres chromosomiques pour les chromosomes 13 et 14 avec cependant une prédominance des formes équilibrées en comparaison au risque théorique de la ségrégation méiotique. Ces résultats suggèrent que l'apoptose pourrait intervenir comme mécanisme régulateur dans l'élimination des spermatozoïdes ayant un déséquilibre chromosomique chez les hommes porteurs d'une translocation chromosomique. Men with a chromosomal translocation produce a significant percentage of unbalanced spermatozoa. In order to determine a correlation between chromosomal anomalies and apoptosis in human sperm, we analysed DNA fragmentation and meiotic segregation in sperm from men with a (13;14) Robertsonian translocation. We studied sperm from 12 (13;14) translocation carriers and 9 proven fertile men with a normal karyotype. Meiotic segregation of chromosomes 13 and 14 was analysed using dual-colour fluorescencein situ hybridization with locus-specific probes for chromosomes 13 and 14. Apoptosis in spermatozoa was measured byin situ TUNEL assay. The meiotic segregation study showed a significantly increased frequency of unbalanced spermatozoa for chromosomes 13 and 14 in (13;14) carriers (15.9%) compared to the control population (1.3%) (p=0.00016). The study of apoptosis showed an increase of DNA fragmentation in (13;14) carriers (34.9%) compared to the control population (13.8%) (p=0.0036). This increased apoptosis was observed in spermatozoa presenting an increase of unbalanced chromosomal anomalies concerning chromosomes 13 and 14, but with a predominance of balanced spermatozoa compared to the theoretical risk of meiotic segregation. These results suggest that apoptosis could be involved as a regulatory mechanism to eliminate unbalanced chromosomal spermatozoa in men with a (13;14) Robertsonian translocation.
  Andrologie 04/2012; 14(2):186-192.
• Source

  Available from: Heather Corbett Etchevers

  Article: ISL1 directly regulates FGF10 transcription during human cardiac outflow formation.

  Christelle Golzio, Emmanuelle Havis, Philippe Daubas, Gregory Nuel, Candice Babarit, Arnold Munnich, Michel Vekemans, Stéphane Zaffran, Stanislas Lyonnet, Heather C Etchevers
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  ABSTRACT: The LIM homeodomain gene Islet-1 (ISL1) encodes a transcription factor that has been associated with the multipotency of human cardiac progenitors, and in mice enables the correct deployment of second heart field (SHF) cells to become the myocardium of atria, right ventricle and outflow tract. Other markers have been identified that characterize subdomains of the SHF, such as the fibroblast growth factor Fgf10 in its anterior region. While functional evidence of its essential contribution has been demonstrated in many vertebrate species, SHF expression of Isl1 has been shown in only some models. We examined the relationship between human ISL1 and FGF10 within the embryonic time window during which the linear heart tube remodels into four chambers. ISL1 transcription demarcated an anatomical region supporting the conserved existence of a SHF in humans, and transcription factors of the GATA family were co-expressed therein. In conjunction, we identified a novel enhancer containing a highly conserved ISL1 consensus binding site within the FGF10 first intron. ChIP and EMSA demonstrated its direct occupation by ISL1. Transcription mediated by ISL1 from this FGF10 intronic element was enhanced by the presence of GATA4 and TBX20 cardiac transcription factors. Finally, transgenic mice confirmed that endogenous factors bound the human FGF10 intronic enhancer to drive reporter expression in the developing cardiac outflow tract. These findings highlight the interest of examining developmental regulatory networks directly in human tissues, when possible, to assess candidate non-coding regions that may be responsible for congenital malformations.
  PLoS ONE 01/2012; 7(1):e30677. · 4.09 Impact Factor
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  Available from: Heather Corbett Etchevers

  Article: CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome.

  Christine S Van Der Werf, Tara D Wabbersen, Nai-Hua Hsiao, Joana Paredes, Heather C Etchevers, Peter M Kroisel, Dick Tibboel, Candice Babarit, Richard A Schreiber, Edward J Hoffenberg, [......], Sirkka L Zeder, Isabella Ceccherini, Stanislas Lyonnet, Ana S Ribeiro, Raquel Seruca, Gerard J Te Meerman, Sven C D van Ijzendoorn, Iain T Shepherd, Joke B G M Verheij, Robert M W Hofstra
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  ABSTRACT: Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190-280 cm. They also are born with intestinal malrotation. Because CSBS occurs in many consanguineous families, it is considered to be an autosomal-recessive disorder. We aimed to identify and characterize the genetic factor causing CSBS. We performed homozygosity mapping using 610,000 K single-nucleotide polymorphism arrays to analyze the genomes of 5 patients with CSBS. After identifying a gene causing the disease, we determined its expression pattern in human embryos. We also overexpressed forms of the gene product that were and were not associated with CSBS in Chinese Hamster Ovary and T84 cells and generated a zebrafish model of the disease. We identified loss-of-function mutations in Coxsackie- and adenovirus receptor-like membrane protein (CLMP) in CSBS patients. CLMP is a tight-junction-associated protein that is expressed in the intestine of human embryos throughout development. Mutations in CLMP prevented its normal localization to the cell membrane. Knock-down experiments in zebrafish resulted in general developmental defects, including shortening of the intestine and the absence of goblet cells. Because goblet cells are characteristic for the midintestine in zebrafish, which resembles the small intestine in human beings, the zebrafish model mimics CSBS. Loss-of-function mutations in CLMP cause CSBS in human beings, likely by interfering with tight-junction formation, which disrupts intestinal development. Furthermore, we developed a zebrafish model of CSBS.
  Gastroenterology 12/2011; 142(3):453-462.e3. · 11.68 Impact Factor
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  Available from: Sylvie Hanu Manouvrier

  Article: Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans.

  Loïc de Pontual, Evelyn Yao, Patrick Callier, Laurence Faivre, Valérie Drouin, Sandra Cariou, Arie Van Haeringen, David Geneviève, Alice Goldenberg, Myriam Oufadem, Sylvie Manouvrier, Arnold Munnich, Joana Alves Vidigal, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude, Andrea Ventura, Jeanne Amiel
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  ABSTRACT: MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
  Nature Genetics 09/2011; 43(10):1026-30. · 35.53 Impact Factor
• Article: KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.

  Audrey Putoux, Sophie Thomas, Karlien L M Coene, Erica E Davis, Yasemin Alanay, Gönül Ogur, Elif Uz, Daniela Buzas, Céline Gomes, Sophie Patrier, [......], Nicolas Goudin, Stanislas Lyonnet, Férechté Encha-Razavi, Jean-Pierre Siffroi, Mark Winey, Nicholas Katsanis, Marie Gonzales, Michel Vekemans, Philip L Beales, Tania Attié-Bitach
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  ABSTRACT: KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.
  Nature Genetics 06/2011; 43(6):601-6. · 35.53 Impact Factor
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  Available from: Heather Corbett Etchevers

  Article: Germline gain-of-function mutations of ALK disrupt central nervous system development.

  Loïc de Pontual, Dania Kettaneh, Christopher T Gordon, Myriam Oufadem, Nathalie Boddaert, Melissa Lees, Laurent Balu, Eric Lachassinne, Andy Petros, Julie Mollet, Louise C Wilson, Arnold Munnich, Laurence Brugière, Olivier Delattre, Michel Vekemans, Heather Etchevers, Stanislas Lyonnet, Isabelle Janoueix-Lerosey, Jeanne Amiel
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  ABSTRACT: Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.
  Human Mutation 03/2011; 32(3):272-6. · 5.69 Impact Factor
• Article: Dissection of the MYCN locus in Feingold syndrome and isolated oesophageal atresia.

  Marie Cognet, Agnés Nougayrede, Valérie Malan, Patrick Callier, Celia Cretolle, Laurence Faivre, David Genevieve, Alice Goldenberg, Delphine Heron, Sandra Mercier, Nicole Philip, Sabine Sigaudy, Alain Verloes, Sabine Sarnacki, Arnold Munnich, Michel Vekemans, Stanislas Lyonnet, Heather Etchevers, Jeanne Amiel, Loïc de Pontual
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  ABSTRACT: Feingold syndrome (FS) is a syndromic microcephaly entity for which MYCN is the major disease-causing gene. We studied the expression pattern of MYCN at different stages of human embryonic development and collected a series of 17 FS and 12 isolated oesophageal atresia (IOA) cases. An MYCN gene deletion/mutation was identified in 47% of FS cases exclusively. We hypothesized that mutations or deletions of highly conserved non-coding elements (HCNEs) at the MYCN locus could lead to its misregulation and thereby to FS and/or IOA. We subsequently sequenced five HCNEs at the MYCN locus and designed a high-density tiling path comparative genomic hybridization array of 3.3 Mb at the MYCN locus. We found no mutations or deletions in this region, supporting the hypothesis of genetic heterogeneity in FS.
  European journal of human genetics: EJHG 01/2011; 19(5):602-6. · 3.56 Impact Factor
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  Available from: Heather Corbett Etchevers

  Article: Dissection of the MYCN locus in Feingold syndrome and isolated oesophageal atresia

  Marie Cognet, Agnès Nougayrede, Valérie Malan, Patrick Callier, Celia Cretole, Laurence Faivre, David Genevieve, Alice Goldenberg, Delphine Heron, Sandra Mercier, Nicole Philip, Sabine Sigaudy, Alain Verloes, Sabine Sarnaki, Arnold Munnich, Michel Vekemans, Stanislas Lyonnet, Heather Etchevers, Jeanne Amiel, Loïc De Pontual
  European journal of human genetics: EJHG 01/2011; · 3.56 Impact Factor
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  Available from: Tania Attie-Bitach

  Article: BBS10 mutations are common in 'Meckel'-type cystic kidneys.

  Audrey Putoux, Soumaya Mougou-Zerelli, Sophie Thomas, Nadia Elkhartoufi, Sophie Audollent, Martine Le Merrer, Augusta Lachmeijer, Sabine Sigaudy, Annie Buenerd, Carla Fernandez, Anne-Lise Delezoide, Marie-Claire Gubler, Rémi Salomon, Ali Saad, Marie-Pierre Cordier, Michel Vekemans, Raymonde Bouvier, Tania Attie-Bitach
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  ABSTRACT: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic disorder characterised by progressive retinal dystrophy, obesity, hypogenitalism, learning difficulties, renal abnormalities and postaxial polydactyly, with only the last two antenatally observable. BBS is inherited as an autosomal recessive disorder, and 14 genes have been identified to date (BBS1-BBS14). In addition, a complex digenic inheritance has been established in some families. Mutations of the BBS10 gene on chromosome 12q21.2 account for 20% of BBS cases. Given the fact that mutations in BBS genes have already been found in Meckel-like fetuses, and in light of the major contribution of BBS10 to BBS, the BBS10 gene was sequenced in 20 fetal cases and a child diagnosed antenatally presenting with characteristic renal anomalies and polydactyly, but without biliary dysgenesis. Recessive mutations were identified at the BBS10 locus in five cases: four fetuses and a child. Interestingly, one of them had situs ambiguus, a rare feature in BBS. In the child, BBS gene screening identified a heterozygous BBS6 nonsense mutation in addition to the homozygous BBS10 mutation, in accordance with the suggested multigenic inheritance of the disease. These results confirm that BBS is underdiagnosed antenatally and should systematically be suspected in fetuses with severe cystic kidneys leading to oligoamnios and fetal or perinatal death. Moreover, this study confirms the high frequency of BBS10 mutations, particularly of the p.Cys91LeufsX5 allele, including severe lethal cases.
  Journal of Medical Genetics 12/2010; 47(12):848-52. · 6.36 Impact Factor
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  Available from: Heather Corbett Etchevers

  Article: High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy.

  Sophie Thomas, Ferechté Encha-Razavi, Louise Devisme, Heather Etchevers, Bettina Bessieres-Grattagliano, Géraldine Goudefroye, Nadia Elkhartoufi, Emilie Pateau, Amale Ichkou, Maryse Bonnière, [......], Christine Bole Feysot, Patrick Nitschke, Nadia Leticee, Arnold Munnich, Stanislas Lyonnet, Peter Wookey, Gabor Gyapay, Bernard Foliguet, Michel Vekemans, Tania Attié-Bitach
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  ABSTRACT: Rare lethal disease gene identification remains a challenging issue, but it is amenable to new techniques in high-throughput sequencing (HTS). Cerebral proliferative glomeruloid vasculopathy (PGV), or Fowler syndrome, is a severe autosomal recessive disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels leading to hydranencephaly. In three multiplex consanguineous families, genome-wide SNP analysis identified a locus of 14 Mb on chromosome 14. In addition, 280 consecutive SNPs were identical in two Turkish families unknown to be related, suggesting a founder mutation reducing the interval to 4.1 Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of seven families. Due to technical constraints related to the disease, the average coverage was only 7×. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a 12 transmembrane domain-containing putative transporter. A striking absence of alpha-smooth muscle actin immunostaining in abnormal vessels in fetal PGV brains, suggests a deficit in pericytes, cells essential for capillary stabilization and remodeling during brain angiogenesis. This is the first lethal disease-causing gene to be identified by comprehensive HTS of an entire linkage interval.
  Human Mutation 10/2010; 31(10):1134-41. · 5.69 Impact Factor
• Article: Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.

  Valérie Malan, Diana Rajan, Sophie Thomas, Adam C Shaw, Hélène Louis Dit Picard, Valérie Layet, Marianne Till, Arie van Haeringen, Geert Mortier, Sheela Nampoothiri, Silvija Puseljić, Laurence Legeai-Mallet, Nigel P Carter, Michel Vekemans, Arnold Munnich, Raoul C Hennekam, Laurence Colleaux, Valérie Cormier-Daire
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  ABSTRACT: By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.
  The American Journal of Human Genetics 08/2010; 87(2):189-98. · 10.60 Impact Factor
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  Available from: Joseph Gleeson

  Article: Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.

  Enza Maria Valente, Clare V Logan, Soumaya Mougou-Zerelli, Jeong Ho Lee, Jennifer L Silhavy, Francesco Brancati, Miriam Iannicelli, Lorena Travaglini, Sveva Romani, Barbara Illi, [......], Chris Inglehearn, Ali Saad, Adila Alkindy, Sophie Thomas, Michel Vekemans, Bruno Dallapiccola, Nicholas Katsanis, Colin A Johnson, Tania Attié-Bitach, Joseph G Gleeson
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  ABSTRACT: Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
  Nature Genetics 07/2010; 42(7):619-25. · 35.53 Impact Factor
• Article: PAX2 mutations in fetal renal hypodysplasia.

  Jelena Martinovic-Bouriel, Alexandra Benachi, Maryse Bonnière, Nora Brahimi, Chantal Esculpavit, Nicole Morichon, Michel Vekemans, Corinne Antignac, Rémi Salomon, Féréchté Encha-Razavi, Tania Attié-Bitach, Marie-Claire Gubler
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  ABSTRACT: Papillorenal syndrome also known as renal-coloboma syndrome (OMIM 120330) is an autosomal dominant condition comprising optic nerve anomaly and renal oligomeganephronic hypoplasia. This reduced number of nephron generations with compensatory glomerular hypertrophy leads towards chronic insufficiency with renal failure. We report on two fetuses with PAX2 mutations presenting at 24 and 18 weeks' gestation, respectively, born into two different sibships. In our first patient, termination of pregnancy was elected for anhydramnios and suspicion of renal agenesis in the healthy couple with an unremarkable previous clinical history. This fetus had bilateral asymmetric kidney anomalies including a small multicystic left kidney, and an extremely hypoplastic right kidney. Histology showed dysplastic lesions in the left kidney, contrasting with rather normal organization in the hypoplastic right kidney. Ocular examination disclosed bilateral optic nerve coloboma. The association of these anomalies, highly suggestive of the papillorenal syndrome, led us to perform the molecular study of the PAX2 gene. Direct sequencing of the PAX2 coding sequence identified a de novo single G deletion of nucleotide 935 in exon 3 of the PAX2 resulting in a frameshift mutation (c.392delG, p.Ser131Thrfs*28). In the second family, the presence of a maternally inherited PAX2 mutation led to a decision for termination of pregnancy. The 18-week gestation fetus presented the papillorenal syndrome including hypoplastic kidneys and optic nerve coloboma. In order to address the PAX2 involvement in isolated renal "disease," 18 fetuses fulfilling criteria were screened: 10/18 had uni- or bilateral agenesis, 6/18 had bilateral multicystic dysplasia with enlarged kidneys, and 2/18 presented bilateral severe hypodysplasia confirmed on fetopathological examination. To the best of our knowledge, our first patient represents an unreported fetal diagnosis of papillorenal syndrome, and another example of the impact of oriented fetopathological examination in genetic counseling of the parents.
  American Journal of Medical Genetics Part A 04/2010; 152A(4):830-5. · 2.39 Impact Factor
• Article: [Trisomy 21: fifty years between medicine and science].

  Catherine Turleau, Michel Vekemans
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  ABSTRACT: Fifty years after the discovery of the etiology of Down syndrome, trisomy 21 remains the model of choice for studying human diseases resulting from the presence of a chromosome or a chromosome segment in excess. In this review, mechanisms of aneuploidy occurrence and consequences of genomic imbalances will be mainly discussed. The study of genetic markers showed that trisomy 21 results in 90% of cases from an error during maternal meiosis. Approximately 8% of cases result from an error during paternal meiosis and in 2% of cases there is a postzygotic mitotic nondisjunction. The biological basis of the effect of maternal age remains largely unknown. The absence of genetic recombination between homologous chromosomes or the presence of an exchange in telomeric position are two risk factors of non-disjunction observed in young women. Non-disjunctions associated with pericentromeric exchanges are observed with an increase in maternal age. The study of mouse models and patients with partial trisomy 21, combined with advances in knowledge of the physical map and the transcriptome, identified genes directly or indirectly involved in the pathogenesis of Down syndrome. The recent description of metabolic pathways controlled by RCAN1 and DYRK1A genes which may be involved in many biological processes and phenotypes associated with trisomy 21 allows to consider new therapeutic strategies.
  Medecine sciences: M/S 03/2010; 26(3):267-72. · 0.64 Impact Factor
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  Available from: Heather Corbett Etchevers

  Article: Identification of the IRXB gene cluster as candidate genes in severe dysgenesis of the ocular anterior segment.

  Myriam Chaabouni, Heather Etchevers, Marie Christine De Blois, Patrick Calvas, Marie Christine Waill-Perrier, Michel Vekemans, Serge Pierrick Romana
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  ABSTRACT: Anterior segment ocular dysgenesis (ASOD) is a broad heterogeneous group of diseases detectable at the clinical and molecular level. In a patient with bilateral congenital ASOD including aniridia and aphakia, a complex chromosomal rearrangement, inv(2)(p22.3q12.1)t(2;16)(q12.1;q12.2), was characterized at the molecular level, to identify candidate genes implicated in ASOD. After negative sequencing of the PAX6, FOXC1, and PITX2 genes, we used fluorescence in situ hybridization (FISH) and Southern blot analysis to characterize the chromosomal breakpoints. Candidate genes were selected, and in situ tissue expression analysis was performed on human fetuses and embryos. Molecular analyses showed that the 16q12.2 breakpoint in this rearrangement occurs in a 625-bp region centromeric to the IRX3 gene, which belongs to the IRXB cluster. In situ hybridization expression studies showed that during early human embryonic development, the IRX3 gene is expressed in the anterior segment of the eye. Of interest, it has been shown previously that a highly conserved noncoding region (HCNCR) is located 300 kb centromeric to the IRX3 gene and induces, in a murine transgenic assay, an expression pattern fitting that of the IRX3 gene. The authors propose that the 16q12.2 breakpoint of this complex translocation is causally related to the ocular anterior segment dysgenesis observed in this patient. This translocation is assumed to separate the HCNCR from the IRXB cluster genes, thus deregulating the IRXB cluster and leading to the ASOD observed by a positional effect.
  Investigative ophthalmology & visual science 02/2010; 51(9):4380-6. · 3.43 Impact Factor