Jeanne Amiel

Publications (82)655.15 Total impact

• Article: Phenotypic Spectrum of Simpson-Golabi-Behmel Syndrome in a Series of 42 Cases With a Mutation in GPC3 and Review of the Literature.

  Edouard Cottereau, Isabelle Mortemousque, Marie-Pierre Moizard, Lydie Bürglen, Didier Lacombe, Brigitte Gilbert-Dussardier, Sabine Sigaudy, Odile Boute, Albert David, Laurence Faivre, [......], Pierre Sarda, Marjolaine Willems, Adeline Jacquinet, Ilham Ratbi, Jenneke VAN DEN Ende, Marylin Lackmy-Port Lis, Alice Goldenberg, Dominique Bonneau, Sylvie Rossignol, Annick Toutain
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  ABSTRACT: Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates. © 2013 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part C Seminars in Medical Genetics 04/2013; · 4.06 Impact Factor
• Article: Clinical and Molecular Spectrum of Renal Malformations in Kabuki Syndrome.

  Jean-Benoît Courcet, Laurence Faivre, Caroline Michot, Antoine Burguet, Stéphanie Perez-Martin, Eudeline Alix, Jeanne Amiel, Clarisse Baumann, Marie-Pierre Cordier, Valérie Cormier-Daire, [......], Catherine Vincent-Delorme, Christiane Mousson, Sandrine Vinault, Christine Binquet, Frédéric Huet, Pierre Sarda, Rémi Salomon, Stanislas Lyonnet, Damien Sanlaville, David Geneviève
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  ABSTRACT: OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.
  The Journal of pediatrics 03/2013; · 4.02 Impact Factor
• Source

  Available from: Jamal Ghoumid

  Article: ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome.

  Jamal Ghoumid, Loïc Drevillon, Seyedeh Maryam Alavi-Naini, Nadège Bondurand, Marlène Rio, Audrey Briand-Suleau, Mayssa Nasser, Linda Goodwin, Patrick Raymond, Constantin Yanicostas, Michel Goossens, Stanislas Lyonnet, David Mowat, Jeanne Amiel, Nadia Soussi-Yanicostas, Irina Giurgea
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  ABSTRACT: Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2.In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro, and p.His1045Arg, identified in the highly conserved C-zinc finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects, or HSCR. In-vitro studies showed that all three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of zebrafish morphant technology, we performed rescue experiments using wild-type and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed.Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2-mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Article: FOX gene cluster defects in alveolar capillary dysplasia associated with congenital heart disease.

  Daniela Laux, Valérie Malan, Fanny Bajolle, Younes Boudjemline, Jeanne Amiel, Damien Bonnet
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  ABSTRACT: OBJECTIVE: The objective was to report two new patients with the diagnosis of alveolar capillary dysplasia and congenital heart disease, to describe the associated cardiac defects seen in these cases and in the literature, and to consider recent genetic advances concerning the FOX transcription factor gene cluster in chromosome 16q24.1q24.2. METHODS: We retrospectively analysed the records of all patients with congenital heart disease and alveolar capillary dysplasia seen in the Pediatric Cardiology Department between 2005 and 2010. We reviewed all literature published in the English language relating to cases of alveolar capillary dysplasia and congenital heart disease. RESULTS: Two infants with alveolar capillary dysplasia and cardiac malformation were identified: one had an atrioventricular septal defect and a de novo balanced reciprocal translocation t(1;16)(q32;q24), the second infant had a ventricular septal defect. Analysis of 31 cases of the literature including these new cases showed a predominant association of alveolar capillary dysplasia with obstructive left heart disease (35%), as well as an atrioventricular septal defect (29%). FOX gene cluster defects were identified in eight of these patients. Discussion Genetic background of alveolar capillary dysplasia is discussed in the light of the balanced reciprocal translocation t(1;16)(q32;q24) identified in the first child of this report. Alveolar capillary dysplasia should be suspected in neonates with congenital heart disease and unexpectedly elevated pulmonary vascular resistances, especially in cases of obstructive left heart disease or atrioventricular septal defect. Detecting FOX gene cluster defects should be considered in infants with alveolar capillary dysplasia with or without congenital heart disease.
  Cardiology in the Young 01/2013; · 0.76 Impact Factor
• Article: Contributions of PHOX2B in the Pathogenesis of Hirschsprung Disease.

  Raquel María Fernández, Yves Mathieu, Berta Luzón-Toro, Rocío Núñez-Torres, Antonio González-Meneses, Guillermo Antiñolo, Jeanne Amiel, Salud Borrego
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  ABSTRACT: Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18) in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype.
  PLoS ONE 01/2013; 8(1):e54043. · 4.09 Impact Factor
• 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
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  Available from: Bert Callewaert

  Article: In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome.

  Virginie Carmignac, Julien Thevenon, Lesley Adès, Bert Callewaert, Sophie Julia, Christel Thauvin-Robinet, Lucie Gueneau, Jean-Benoit Courcet, Estelle Lopez, Katherine Holman, [......], Frédéric Huet, Guillaume Jondeau, Gwenaëlle Collod-Beroud, Christophe Beroud, Jeanne Amiel, Valérie Cormier-Daire, Jean-Baptiste Rivière, Catherine Boileau, Anne De Paepe, Laurence Faivre
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  ABSTRACT: Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.
  The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
• Article: Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression.

  Mayumi Nagashimada, Hiroshi Ohta, Chong Li, Kazuki Nakao, Toshihiro Uesaka, Jean-François Brunet, Jeanne Amiel, Delphine Trochet, Teruhiko Wakayama, Hideki Enomoto
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  ABSTRACT: The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine β-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.
  The Journal of clinical investigation 08/2012; 122(9):3145-58. · 15.39 Impact Factor
• Article: Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia.

  Lilia Kraoua, Hubert Journel, Philippe Bonnet, Jeanne Amiel, Nathalie Pouvreau, Clarisse Baumann, Alain Verloes, Hélène Cavé
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  ABSTRACT: Recently, germline mutations of NRAS have been shown to be associated with Noonan syndrome (NS), a relatively common developmental disorder characterized by short stature, congenital heart disease, and distinctive facial features. We report on the mutational analysis of NRAS in a cohort of 125 French patients with NS and no known mutation for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1, BRAF, and SHOC2. The c.179G>A (p.G60E) mutation was identified in two patients with typical NS, confirming that NRAS germline mutations are a rare cause of this syndrome. We also screened our cohort of 95 patients with juvenile myelomonocytic leukemia (JMML). Among 17 patients with NRAS-mutated JMML, none had clinical features suggestive of NS. None of the 11 JMML patients for which germline DNA was available had a constitutional NRAS mutation. © 2012 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 08/2012; 158A(10):2407-11. · 2.39 Impact Factor
• Article: MicroRNAs in genetic disease: rethinking the dosage.

  Alexandra Henrion-Caude, Muriel Girard, Jeanne Amiel
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  ABSTRACT: To date, the general assumption was that most mutations interested protein-coding genes only. Thus, only few illustrations have mentioned here that mutations may occur in non-protein coding genes such as microRNAs (miRNAs). We thus report progress in delineating their contribution as phenotypic modulators, genetic switches and fine-tuners of gene expression. We reasoned that browsing their contribution to genetic disease may provide a framework for understanding the proper requirements to devise miRNA-based therapy strategies, in particular the relief of an appropriate dosage. Gain and loss of function of miRNA enforce the need to respectively antagonize or supply the miRNAs. We further categorized human disease according to the different ways in which the miRNA was altered arising either de novo, or inherited whether as a mendelian or as an epistatic trait, uncovering its role in epigenetics. We discuss how improving our knowledge on the contribution of miRNAs to genetic disease may be beneficial to devise appropriate gene therapy strategies.
  Current Gene Therapy 08/2012; 12(4):292-300. · 3.39 Impact Factor
• Article: Two independent de novo mutations as a cause for neurofibromatosis type 1 and Noonan syndrome in a single family.

  Eric Pasmant, Jeanne Amiel, Diana Rodriguez, Michel Vidaud, Dominique Vidaud, Béatrice Parfait
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  ABSTRACT: Here we report on a family with two siblings born to unrelated healthy parents, one with neurofibromatosis type 1 (NF1) and the other with Noonan syndrome (NS). Molecular investigations performed on the NF1 and PTPN11 genes showed two independent de novo mutations as a cause for NF1 in the NF1 proband and NS in her affected brother. Both de novo mutations were potentially of paternal origin, given the advanced paternal age at the time of conception.
  American Journal of Medical Genetics Part A 07/2012; 158A(9):2290-1. · 2.39 Impact Factor
• Article: NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications.

  Orianne Philippe, Marlène Rio, Valérie Malan, Hilde Van Esch, Geneviève Baujat, Nadia Bahi-Buisson, Vassili Valayannopoulos, Roseline Gesny, Jean-Paul Bonnefont, Arnold Munnich, Guy Froyen, Jeanne Amiel, Nathalie Boddaert, Laurence Colleaux
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  ABSTRACT: One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-κB. Yet, whether NF-κB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-κB signalling. These observations prompted us to hypothesise that NF-κB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-κB activation. Quantitative RT-PCR experiments and κB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-κB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-κB signalling in astroglial cells for normal myelin formation of the central nervous system.European Journal of Human Genetics advance online publication, 18 July 2012; doi:10.1038/ejhg.2012.140.
  European journal of human genetics: EJHG 07/2012; · 3.56 Impact Factor
• Article: Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability.

  Julien Thevenon, Estelle Lopez, Boris Keren, Delphine Heron, Cyril Mignot, Cecilia Altuzarra, Mylène Béri-Dexheimer, Céline Bonnet, Eloi Magnin, Lydie Burglen, [......], Virginie Carmignac, Patrick Callier, Nathalie Marle, Anne-Laure Mosca-Boidron, Virginie Roze, Bernard Aral, Ferechte Razavi, Philippe Jonveaux, Laurence Faivre, Christel Thauvin-Robinet
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  ABSTRACT: Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited. Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing. Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation. The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.
  Journal of Medical Genetics 06/2012; 49(6):400-8. · 6.36 Impact Factor
• Article: Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease.

  Anne-Sophie Jannot, Jeanne Amiel, Anna Pelet, Francesca Lantieri, Raquel M Fernandez, Joke B G M Verheij, Merce Garcia-Barcelo, Stacey Arnold, Isabella Ceccherini, Salud Borrego, Robert M W Hofstra, Paul K H Tam, Arnold Munnich, Aravinda Chakravarti, Françoise Clerget-Darpoux, Stanislas Lyonnet
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  ABSTRACT: Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.
  European journal of human genetics: EJHG 03/2012; 20(9):917-20. · 3.56 Impact Factor
• Article: miRNA, Development and Disease.

  Jeanne Amiel, Loïc de Pontual, Alexandra Henrion-Caude
  Advances in genetics 01/2012; 80:1-36. · 3.39 Impact Factor
• Source

  Available from: Sophie Thomas

  Article: Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.

  Sabina Benko, Christopher T Gordon, Delphine Mallet, Rajini Sreenivasan, Christel Thauvin-Robinet, Atle Brendehaug, Sophie Thomas, Ove Bruland, Michel David, Marc Nicolino, [......], Frédéric Huet, Anders Molven, Frédérique Dijoud, Arnold Munnich, Laurence Faivre, Jeanne Amiel, Vincent Harley, Gunnar Houge, Yves Morel, Stanislas Lyonnet
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  ABSTRACT: The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off. Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter. These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.
  Journal of Medical Genetics 11/2011; 48(12):825-30. · 6.36 Impact Factor
• Article: Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

  Sandra Whalen, Delphine Héron, Thierry Gaillon, Oana Moldovan, Massimiliano Rossi, Françoise Devillard, Fabienne Giuliano, Gabriela Soares, Michelle Mathieu-Dramard, Alexandra Afenjar, [......], Audrey Putoux, Damien Sanlaville, Richard Fischer, Loïc Drévillon, Audrey Briand-Suleau, Corinne Metay, Michel Goossens, Jeanne Amiel, Aurelia Jacquette, Irina Giurgea
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  ABSTRACT: Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS.
  Human Mutation 11/2011; 33(1):64-72. · 5.69 Impact Factor
• Source

  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
• Source

  Available from: Tania Attie-Bitach

  Article: RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects.

  Cécile Jeanpierre, Guillaume Macé, Mélanie Parisot, Vincent Morinière, Audrey Pawtowsky, Marion Benabou, Jelena Martinovic, Jeanne Amiel, Tania Attié-Bitach, Anne-Lise Delezoide, Philippe Loget, Patricia Blanchet, Dominique Gaillard, Marie Gonzales, Wassila Carpentier, Patrick Nitschke, Frédéric Tores, Laurence Heidet, Corinne Antignac, Rémi Salomon
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  ABSTRACT: The RET/GDNF signalling pathway plays a crucial role during development of the kidneys and the enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. To characterise better the involvement of RET and GDNF in kidney development defects, a series of 105 fetuses with bilateral defects, including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney, was studied. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs, and RET intron 1 were analysed. Copy number variations at these loci were also investigated. The study identified: (1) a low frequency (<7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (2) no GDNF mutation; (3) similar allele frequencies in patients and controls for most single nucleotide polymorphism variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs 2%, p=0.01); (4) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (5) absence of copy number variations. These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.
  Journal of Medical Genetics 07/2011; 48(7):497-504. · 6.36 Impact Factor
• Article: Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4.

  Vassili Valayannopoulos, Caroline Michot, Diana Rodriguez, Laurence Hubert, Yoann Saillour, Philippe Labrune, Jocelyne de Laveaucoupet, Francis Brunelle, Jeanne Amiel, Stanislas Lyonnet, Ferechté Enza-Razavi, Tania Attié-Bitach, Didier Lacombe, Nadia Bahi-Buisson, Isabelle Desguerre, Jamel Chelly, Lydie Burglen, Nathalie Boddaert, Pascale de Lonlay
  Brain 05/2011; 135(Pt 1):e199; author reply e200. · 9.46 Impact Factor