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51. Duplication of 10q24 locus: broadening the clinical and radiological spectrum

Author: Joris Andrieux, Anna Sowińska-Seidler, Joo Wook Ahn, Elena Pollina, Clarisse Baumann, Chantal Farra, Florence Petit, Sébastien Jacquemont, Muriel Holder-Espinasse, Philippe Jonveaux, Jane A. Hurst, Sylvie Manouvrier-Hanu, Magdalena Socha, Neeti Ghali, Sahar Mansour, Albert David, Anne-Sylvie Valat, Michèle Mathieu-Dramard, Anne Moncla, Annick Toutain, Alain Verloes, Anna Jakubiuk-Tomaszuk, Nayana Lahiri, Estelle Colin, Annick Rossi, David Zhang, Philippe Bourgeot, Aleksander Jamsheer, Fabienne Escande, Marion Gérard, Aurélie Mezel, Valérie Cormier-Daire, Ghislaine Plessis, Christine Patch, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), biology and pathological laboratory, Institut de Génétique Médicale [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Jeanne de Flandre [Lille], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Agricultural University of Krakow, Université de Lorraine (UL), Service de génétique médicale, CHU Amiens-Picardie, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, MLab, Dauphine Recherches en Management (DRM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Wessex Clinical Genetics Service, Wessex clinical genetics service, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Laboratoire de Génétique Chromosomique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Clinical Genetics/EMGO Institute for Health and Care research, Biometrics Research Center, The Hong Kong Polytechnic University [Hong Kong] (POLYU), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Adult, Male, Proteasome Endopeptidase Complex, BTRC, Limb Deformities, Congenital, Locus (genetics), Review Article, Biology, Young Adult, 03 medical and health sciences, Exon, Segmental Duplications, Genomic, Proto-Oncogene Proteins, Gene duplication, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Segmental duplication, Gene Rearrangement, Regulation of gene expression, Comparative Genomic Hybridization, 0303 health sciences, Chromosomes, Human, Pair 10, F-Box Proteins, 030305 genetics & heredity, Infant, Penetrance, Pedigree, Radiography, Wnt Proteins, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Female, Hand Deformities, Congenital, Limb morphogenesis
Abstract: International audience; Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.
Published: 2019
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52. A new case of pcsk1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review

Author: Estelle Colin, Régis Coutant, Dominique Bonneau, Stéphanie Rouleau, Natacha Bouhours-Nouet, Marine Tessarech, Lucie Pépin, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Néonatalogie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), and PRES Université Nantes Angers Le Mans (UNAM)
Subjects: Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, Turkey, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Proprotein convertase 1, Consanguinity, Hypoglycemia, Endocrine System Diseases, Biochemistry, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Endocrinology, Hypogonadotropic hypogonadism, 030225 pediatrics, Internal medicine, Central hypothyroidism, medicine, Humans, Obesity, business.industry, Homozygote, Biochemistry (medical), Exons, Micropenis, medicine.disease, 3. Good health, 030104 developmental biology, Proprotein Convertase 1, Codon, Nonsense, Child, Preschool, Mutation, Diabetes insipidus, business, Proinsulin, Postprandial Hypoglycemia
Abstract: International audience; Issue: To report a homozygous pathogenic variant in PCSK1 in a boy affected with proprotein convertase 1/3 (PC1/3) deficiency.Case description and literature review: A male infant born to consanguineous Turkish parents presented in the first week of life with transient central diabetes insipidus, watery diarrhea, micropenis due to hypogonadotropic hypogonadism and GH deficiency, and transient asymptomatic hypoglycemia. Further endocrine defects gradually appeared, including central hypothyroidism and mild central hypocortisolism (at 1 yr), central diabetes insipidus that reappeared progressively (at 2.5 yr), and obesity (at 2 yr). Whole exome sequencing revealed a homozygous nonsense pathogenic variant (NM_000439.4) c. 595 C>T in exon 5 of PCSK1, not yet reported in cases of proprotein convertase 1/3 (PC1/3) deficiency. To date, 26 cases of PC1/3 deficiency have been reported in the literature. All individuals had early and severe malabsorptive diarrhea and 83% had polyuria-polydipsia syndrome (before 5 yr). Most (79%) had early-onset obesity. Various endocrine disorders were present, including growth hormone deficiency (44%), mild central hypothyroidism (56%), central hypogonadism (44%), central hypocortisolism (57%), and postprandial hypoglycemia (52%). When described (n=15), proinsulin levels were consistently high: between 8 and 154 times the upper limit of normal (mean 74).Conclusion: We described a homozygous nonsense pathogenic variant (NM_000439.4) c. 595 C>T in exon 5 of PCSK1 in a boy with congenital proprotein convertase 1/3 deficiency. Elevated proinsulin could be useful in the diagnosis of this condition.
Published: 2019
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53. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, Gabriella Silvestri (ORCID:0000-0002-1950-1468), Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, and Gabriella Silvestri (ORCID:0000-0002-1950-1468)
Abstract: AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
Published: 2019

54. Karyotype is not dead (yet)!

Author: Florence Demurger, Hubert Journel, Mélanie Fradin, Vincent Jauffret, Sylvie Odent, Chloé Quélin, Dominique Martin-Coignard, Marc-Antoine Belaud-Rotureau, Elouan Cherot, Sylvie Jaillard, Estelle Colin, Laurent Pasquier, Linda Akloul, Josette Lucas, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
Subjects: Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Genetic counseling, Karyotype, Chromosomal translocation, Chromosomal rearrangement, Disease, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Developmental abnormalities, Genetics, Humans, Balanced translocation, Exome, In Situ Hybridization, Fluorescence, Genetics (clinical), Exome sequencing, Genetic counselling, Gene disrupted, Genetic Diseases, Inborn, Infant, Newborn, General Medicine, 3. Good health, 030104 developmental biology, Karyotyping, 030220 oncology & carcinogenesis, Female
Abstract: International audience; Background: While array-comparative genomic hybridization (a-CGH) and next-generation sequencing (NGS or exome) technologies have swiftly spread throughout the medical field, karyotype has gradually lost its leading role among genetic tests. Several international guidelines recommend starting with a-CGH screening then going on with exome analysis when investigating a patient with intellectual disability (ID) and no precise clinical diagnosis. A-CGH and whole exome sequencing increase etiologic diagnoses rate up to 30% in case of ID. However, physicians have to deal with the lack of qualitative information of the genome. Especially, exome and a-CGH analysis fail to detect chromosomal rearrangements because breakpoints are either located in introns or not associated with a gain or loss of genetic material. If these technologies cannot easily identify chromosomal translocations or inversions which sometimes split a gene, karyotype can. Discussion: For the 5 cases described, karyotype provided the right diagnosis for a Mendelian disease while molecular analysis remained unsuccessful. We conclude that when a Mendelian disease is strongly suggested clinically, if molecular analysis is normal, it could be very useful to carry out a karyotype in order to demonstrate a chromosomal rearrangement involving the targeted gene. If this gene is disrupted, the physician can confirm the suspected disease and give appropriate genetic counseling. Summary This article aims at keeping in mind that karyotype, this old-fashioned genetic tool, can still remain powerful and useful within some genetic issues. Even in this modern period of whole exome sequencing, young geneticists should know that karyotype remains a powerful and cheap technology, available throughout the world and can still do a lot for families
Published: 2016
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55. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Author: Karin Weiss, Hayley P. Lazar, Alina Kurolap, Ariel F. Martinez, Tamar Paperna, Lior Cohen, Marie F. Smeland, Sandra Whalen, Solveig Heide, Boris Keren, Pauline Terhal, Melita Irving, Motoki Takaku, John D. Roberts, Robert M. Petrovich, Samantha A. Schrier Vergano, Amy Kenney, Hanne Hove, Elizabeth DeChene, Shane C. Quinonez, Estelle Colin, Alban Ziegler, Melissa Rumple, Mahim Jain, Danielle Monteil, Elizabeth R. Roeder, Kimberly Nugent, Arie van Haeringen, Michael Gambello, Avni Santani, Līvija Medne, Bryan Krock, Cara M. Skraban, Elaine H. Zackai, Holly A. Dubbs, Thomas Smol, Jamal Ghoumid, Michael J. Parker, Michael Wright, Peter Turnpenny, Jill Clayton-Smith, Kay Metcalfe, Hitoshi Kurumizaka, Bruce D. Gelb, Hagit Baris Feldman, Philippe M. Campeau, Maximilian Muenke, Paul A. Wade, and Katherine Lachlan
Subjects: Genetics (clinical)
Published: 2020
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56. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author: Anne Boland, Alain Verloes, Jean-François Deleuze, Amélie Piton, Robert Olaso, Jean-Louis Mandel, Laura Mary, Laurence Faivre, Christine Coubes, Bénédicte Gérard, Elise Schaefer, David Geneviève, Claire Feger, Irina Giurgea, Estelle Colin, Francesca Mattioli, Salima El Chehadeh, Dana Timbolschi, Yline Capri, Jennifer Fabre-Teste, Elsa Nourisson, Elisabeth Flori, Magalie Barth, Laurence Perrin, Claire Redin, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Collège de France (CdF (institution)), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de cytogénétique, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Génotypage, Institut de Génomique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Intellectual disability, Disease, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Transcription Factor 4, MESH: Young adult, MESH: Child, Hyperventilation, 10. No inequality, Child, MESH: Transcription factor 4 / genetics, Genetics (clinical), MESH: Hyperventilation / genetics, Sanger sequencing, Mutation, High-Throughput Nucleotide Sequencing, TCF4, 3. Good health, Phenotype, MESH: Facies, Child, Preschool, Cohort, symbols, Female, MESH: Hight-throughput Nucleotide sequencing, Adult, MESH: Mutation, Adolescent, MESH: Phenotype, Article, MESH: Child, preschool, 03 medical and health sciences, symbols.namesake, Young Adult, Genetics, medicine, Humans, MESH: Adolescent, MESH: Humans, MESH: Hyperventilation / diagnosis, business.industry, Facies, MESH: Adult, medicine.disease, MESH: Male, MESH: Intellectual Disability / pathology, Human genome, business, Large-Scale Sequencing, MESH: Female
Abstract: IF 3.636 (2017); International audience; High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Published: 2018
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57. Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Author: Edouard Cottereau, Annick Toutain, Estelle Colin, Marie-Pierre Moizard, Martine Raynaud, Sandrine Vonwill, Sylvie Rossignol, Fabienne Giuliano, Udhaya Kotecha, Tiffany Busa, Marie-Laure Vuillaume, Marion Gérard, Jean-Luc Alessandri, Frédéric Brioude, Mathilde Lefevre, Laetitia Lambert, Irène Netchine, Sheela Nampoothiri, Richard, Nicolas, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), IRCER - Axe 3 : organisation structurale multiéchelle des matériaux (IRCER-AXE3), Institut de Recherche sur les CERamiques (IRCER), Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Tours, Université de Tours (UT), Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Unité de Génétique Clinique [CHRU Nancy], Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sir Ganga Ram Hospital, Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human Molecular Genetics, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), IMAXIO, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital l'Archet, Service de Génétique Clinique Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: 0301 basic medicine, Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Genes, X-Linked, Genotype, Coding region, Missense mutation, MESH: Codon, Nonsense, Frameshift Mutation, Genetics (clinical), Genetics, 0303 health sciences, MESH: Frameshift Mutation, Genetic Diseases, X-Linked, Simpson–Golabi–Behmel syndrome, Pedigree, MESH: Arrhythmias, Cardiac, Phenotype, Codon, Nonsense, 030220 oncology & carcinogenesis, Female, Heart Defects, Congenital, MESH: Pedigree, Nonsense mutation, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Gigantism, Frameshift mutation, MESH: Intellectual Disability, 03 medical and health sciences, Glypicans, MESH: Glypicans, Intellectual Disability, medicine, MESH: Genetic Diseases, X-Linked, Humans, Simpson-Golabi-Behmel syndrome, Gene, overgrowth, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Arrhythmias, Cardiac, MESH: Heart Defects, Congenital, medicine.disease, mutations, MESH: Gigantism, MESH: Male, GPC3, X-linked disorder, 030104 developmental biology, MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Overgrowth syndrome, MESH: Female
Abstract: International audience; Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).
Published: 2018
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58. Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia

Author: Sébastien Boulanger, Marga Buzatu, Sandrine Mary, Isabelle Maystadt, Alban Ziegler, Damien Lederer, Marie Deprez, Agnès Guichet, Philippe Clapuyt, Valérie Benoit, Stéphanie Moortgat, Estelle Colin, Dominique Bonneau, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - (SLuc) Centre du cancer, and UCL - (SLuc) Service de radiologie
Subjects: 0301 basic medicine, Male, Adolescent, X-linked intellectual disability, Developmental Disabilities, Disease, Nervous System Malformations, 03 medical and health sciences, Neuroimaging, Next generation sequencing, Intellectual Disability, Cerebellum, Intellectual disability, Genetics, medicine, Missense mutation, Humans, Child, Cerebellar hypoplasia, Genetics (clinical), Oligophrenin 1, business.industry, GTPase-Activating Proteins, Nuclear Proteins, General Medicine, medicine.disease, OPHN1, Pedigree, Cytoskeletal Proteins, 030104 developmental biology, Phenotype, Brain MRI, Speech delay, Mutation, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ventriculomegaly
Abstract: International audience; Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle. Rho protein members play an important role in dendritic growth and in plasticity of excitatory synapses. Here we report on 17 individuals from four unrelated families affected by mild to severe intellectual disability due to OPHN1 mutations without cerebellar anomaly on brain MRI. We describe clinical, genetic and neuroimaging data of affected patients. Among the identified OPHN1 mutations, we report for the first time a missense mutation occurring in a mosaic state. We discuss the intrafamilial clinical variability of the disease and compare our patients with those previously reported. We emphasize the power of next generation techniques (X-exome sequencing, whole-exome sequencing and targeted multi-gene panel) to expand the phenotypic and mutational spectrum of OPHN1-related ID.
Published: 2018
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59. Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Author: Naïg Gueguen, Arnaud Chevrollier, Anne Moncla, Estelle Colin, Vincent Procaccio, Michel Tsimaratos, Christelle Arrondel, Zelal Ekinci, Corinne Antignac, Géraldine Mollet, Brigitte Chabrol, Marc Ferré, Alain Verloes, Valérie Desquiret-Dumas, Agnès Guichet, Laurence Richard, Marie-Claire Gubler, Evelyne Huynh Cong, Nathalie Boddaert, Olivier Gribouval, Olivia Boyer, Laurent Daniel, Benoît Funalot, Dominique Bonneau, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Kocaeli University [Turkey], Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), CHU Limoges, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Univ Angers, Okina
Subjects: Male, Models, Molecular, Pathology, medicine.medical_specialty, Microcephaly, Nephrotic Syndrome, Adolescent, Cell Survival, [SDV]Life Sciences [q-bio], Nephrosis, Kidney Glomerulus, Mitosis, Postnatal microcephaly, Biology, medicine.disease_cause, Microtubules, Article, Cell Line, Cytosol, Intellectual Disability, Genetics, medicine, Humans, Genetics(clinical), Exome, Spindle Poles, Child, Genetics (clinical), Mutation, Podocytes, Homozygote, Brain, Proteins, medicine.disease, Galloway Mowat syndrome, Steroid-resistant nephrotic syndrome, [SDV] Life Sciences [q-bio], Protein Transport, Hernia, Hiatal, Child, Preschool, Nephrotic syndrome
Abstract: International audience; Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.
Published: 2014
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60. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Author: Montserrat Rodríguez-Ballesteros, Laurence Faivre, Pierre-Simon Jouk, Christine Francannet, Damien Sanlaville, Sophie Naudion, Hélène Dollfus, Nicole Philip, Pierre Sarda, Marine Legendre, X. Piguel, Alice Masurel-Paulet, Marie-Ange Delrue, Frédéric Bilan, Aurélia Jacquette, Dominique Bonneau, Catherine Vincent-Delorme, Valérie Layet, Michèle Mathieu-Dramard, Delphine Héron, Sébastien Moutton, Alice Goldenberg, Sophie Julia, Sophie Blesson, Sylvie Odent, Philippe Parent, Chloé Quélin, Estelle Colin, Mélanie Fradin, Anne-Marie Guerrot, David Geneviève, Lucile Pinson, Renaud Touraine, Sabine Sigaudy, Stéphanie Ragot, Didier Lacombe, Massimiliano Rossi, Salima El Chehadeh, Tiffany Busa, Annick Toutain, Stanislas Lyonnet, Véronique Abadie, Bruno Leheup, Dominique Martin-Coignard, Tania Attié-Bitach, Brigitte Gilbert-Dussardier, Sandra Mercier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Endocrinologie [CHU Poitiers], Service Génétique Médicale [CHU Poitiers], French Ministry of Health ID-RCB: 2010-A00700-39, Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Médecine Aérospatiale du Service de Santé des Armées ( IMASSA ), Service de Santé des Armées, Université d'Angers ( UA ) -CHU Angers, Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Bretonneau-CHRU Tours, Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique médicale et cytogénétique [Le Mans], CH Le Mans, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, CHU - HÔTEL-DIEU Clermont-Ferrand, CHU Bordeaux [Bordeaux], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Cardiologie, Pôle DUNE, CHU de Poitiers, Centre d' investigation clinique-plurithématique du CHU de Poitiers, Génétique Médicale, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, université de Bourgogne, GAD, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Central Nervous System, Male, update, Choanal atresia, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Gastroenterology, spectrum, Cohort Studies, CHARGE syndrome, Genotype, Medicine, Child, Genetics (clinical), Coloboma, Genetic disorder, Cranial Nerves, Hypoplasia, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, Child, Preschool, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Anosmia, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, otorhinolaryngologic diseases, Humans, Abnormalities, Multiple, Genetic Testing, Alleles, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, association, DNA Helicases, Infant, medicine.disease, mutations, diagnostic-criteria, 030104 developmental biology, Amino Acid Substitution, Atresia, chd7 gene, proposal, CHARGE Syndrome, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
Published: 2017
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61. Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature

Author: Hélène Dollfus, Stéphane Triau, Sophie Scheidecker, Karl-Heinz Grzeschik, Estelle Colin, Laura Mary, Monique Kohler, Anne-Lise Delezoide, Elisabeth Auberger, Maria Cristina Antal, Marion Gérard, Maria-Paola Lombardi, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Reproduction & Development (AR&D), Human Genetics, Other Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Cardiovascular Sciences, and ACS - Pulmonary hypertension & thrombosis
Subjects: 0301 basic medicine, Male, Genotype, DNA Mutational Analysis, Anterior wall, Autopsy, Prenatal diagnosis, Ultrasonography, Prenatal, 03 medical and health sciences, Fetus, Prenatal Diagnosis, Genetics, medicine, Humans, Prenatal, Genetic Testing, Genetics (clinical), Genetic Association Studies, Genetic testing, Ultrasonography, medicine.diagnostic_test, Growth retardation, business.industry, Induced, Abortion, Membrane Proteins, Abortion, Induced, Anatomy, medicine.disease, Focal dermal hypoplasia, 3. Good health, Diaphragm (structural system), Focal Dermal Hypoplasia, Radiography, 030104 developmental biology, Phenotype, Mutation, Female, business, Acyltransferases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.
Published: 2017
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62. Hematopoietic stem cell transplantation in 29 patientshemizygous for hypomorphic IKBKG/NEMO mutations

Author: Ryuta Nishikomori, Rainer Doffinger, Beatriz Tavares Costa-Carvalho, Andrew R. Gennery, Shinya Sasaki, Erwin W. Gelfand, Shanmuganathan Chandrakasan, Tsubasa Okano, Alberto Olaya-Vargas, Paul Veys, Alfons Krol, Andrea M. Jones, Jean-Laurent Casanova, Etsuro Ito, Waseem Qasim, Thomas Vraetz, Jordan S. Orange, Estelle Colin, Marco Antonio Yamazaki-Nakashimada, Mario Abinun, Nyree Cole, Zeynep Yesim Kucuk, Tayfun Güngör, Chihaya Imai, Capucine Picard, Charline Miot, Steven M. Holland, Stéphane Blanche, Sara Espinosa Padilla, Isabelle Pellier, Despina Moshous, Benedicte Neven, Antonio Condino-Neto, Gulbu Uzel, Jana Pachlopnik Schmid, Smita Y. Patel, Kohsuke Imai, Jérémie Rosain, Jack J. Bleesing, Sophie Dupuis Girod, Stephan Ehl, Jacinta Bustamante, Anthony J. Mancini, Anne Puel, Tokomki Kawai, Stephen Jolles, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Ectodermal dysplasia, Heterozygote, Transplantation Conditioning, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, Biochemistry, Cohort Studies, 03 medical and health sciences, Inside BLOOD Commentary, IKBKG, medicine, Humans, Child, Preschool, Survival rate, IMUNOLOGIA, Immunodeficiency, Inflammation, Transplantation, business.industry, Infant, Newborn, Hematopoietic Stem Cell Transplantation, NF-kappa B, Infant, Cell Biology, Hematology, medicine.disease, Newborn, Inflammatory Bowel Diseases, Survival Analysis, Tissue Donors, 3. Good health, I-kappa B Kinase, 030104 developmental biology, surgical procedures, operative, Phenotype, Treatment Outcome, Child, Preschool, Mutation, Primary immunodeficiency, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of mutations.
Published: 2017
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63. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author: Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge
Subjects: Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract: Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
Published: 2014

64. SLC24A5 Mutations Are Associated with Non-Syndromic Oculocutaneous Albinism

Author: Hubert Journel, Caroline Rooryck, Eric Bieth, Delphine Simon, Eulalie Lasseaux, Françoise Meire, Didier Lacombe, Fanny Morice-Picard, Bart P. Leroy, Sophie Walraedt, Stéphane François, Estelle Colin, Dominique Bonneau, and Benoit Arveiler
Subjects: Male, Ocular albinism, animal structures, Adolescent, Genotype, SLC24A5, Dermatology, Biochemistry, Antiporters, Young Adult, medicine, Humans, Molecular Biology, Genetics, biology, Infant, Cell Biology, medicine.disease, Oculocutaneous albinism, Phenotype, Albinism, Oculocutaneous, Child, Preschool, Mutation, embryonic structures, biology.protein, Female, Non syndromic
Published: 2014
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65. Mutations inWNT10Aare frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

Author: Encarna Guillén-Navarro, Sabine Sigaudy, Christine Coubes, Ghislaine Plessis, Dominique Martin-Coignard, Marc Abramowicz, Philippe Jonveaux, Catherine Vincent-Delorme, Frédéric Vaysse, Isabelle Bailleul-Forestier, Estelle Colin, V. Gaston, Nicolas Chassaing, Didier Lacombe, Bénédicte Demeer, Muriel Holder-Espinasse, Patrick Calvas, Julie Plaisancié, Hélène Dollfus, Eric Bieth, Alain Verloes, and Laurence Faivre
Subjects: Male, Ectodermal dysplasia, Genotype, Molecular Sequence Data, medicine.disease_cause, Compound heterozygosity, Ectodermal Dysplasia, Genetics, medicine, Humans, Amino Acid Sequence, Hypohidrotic ectodermal dysplasia, Genetic Association Studies, Genetics (clinical), Anodontia, Mutation, EDARADD, Edar Receptor, Genetic heterogeneity, business.industry, medicine.disease, Wnt Proteins, Hypodontia, Phenotype, Female, Ectodysplasin A, business, Sequence Alignment
Abstract: Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED. © 2013 Wiley Periodicals, Inc.
Published: 2013
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66. Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α

Author: Eliane, Berrou, Frédéric, Adam, Marilyne, Lebret, Virginie, Planche, Patricia, Fergelot, Odile, Issertial, Isabelle, Coupry, Jean-Claude, Bordet, Paquita, Nurden, Dominique, Bonneau, Estelle, Colin, Cyril, Goizet, Jean-Philippe, Rosa, and Marijke, Bryckaert
Subjects: Adult, Blood Platelets, Male, Talin, Heredity, Platelet Function Tests, Filamins, DNA Mutational Analysis, Intestinal Pseudo-Obstruction, Telomere-Binding Proteins, Integrin alpha2, Integrin beta3, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Activation, Transfection, Shelterin Complex, Cell Line, Phenotype, Periventricular Nodular Heterotopia, Mutation, von Willebrand Factor, Humans, Genetic Predisposition to Disease, Protein Binding, Signal Transduction
Abstract: Dominant mutations of the X-linked filamin A (We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linkedAltogether, our results are consistent with a less binding of mutant FLNa to β
Published: 2016

67. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

Author: Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B. Haack, Salim Khiati, Anne-Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A. Aleck, Lorenzo D. Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N’Guyen, José Antonio Mora-Lorca, Birgit Assmann, Stine Christ, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Antonio Miranda-Vizuete, Georg F. Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau, Emmanuelle Génin, Dominique Campion, Jean-François Dartigues, Jean-François Deleuze, Jean-Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier Quenez, Christian Dina, Céline Bellenguez, Camille Charbonnier -Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gaël Nicolas, Karen Rouault, Delphine Bacq, Anne Boland, Doris Lechner, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Médicale Pédiatrique, Centre hospitalier universitaire de Nantes (CHU Nantes), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), and Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health
Subjects: 0301 basic medicine, Male, Microcephaly, Movement disorders, [SDV]Life Sciences [q-bio], Ubiquitin-Activating Enzymes, Endoplasmic Reticulum, Synaptic Transmission, Exome, Genetics(clinical), Age of Onset, Child, Zebrafish, Genetics (clinical), Caenorhabditis elegans, Genetics, Brain Diseases, Brain Mapping, Movement Disorders, biology, Magnetic Resonance Imaging, Cholinergic Neurons, 3. Good health, Child, Preschool, Female, medicine.symptom, Encephalopathy, Genes, Recessive, 03 medical and health sciences, Intellectual Disability, Report, medicine, Gene silencing, Animals, Humans, Caenorhabditis elegans Proteins, Gene, Ubiquitins, Alleles, Epilepsy, Ubiquitin, Endoplasmic reticulum, Proteins, Fibroblasts, Zebrafish Proteins, biology.organism_classification, medicine.disease, 030104 developmental biology, Mutation
Abstract: International audience; Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.
Published: 2016
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68. Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Author: Arend Bökenkamp, Rajeshree Govender, Amira Davis, Yumi Asakura, Dominique Bonneau, Mattia Gentile, David M. Parham, Clara Myung, Uluç Yiş, Behzad Najafian, Cornelius F. Boerkoel, Mario Giordano, Kunho Choi, Kory Keller, Peter Stenzel, Kimberly Beirnes, Joel Charrow, Glenda Hendson, Estelle Colin, Milena Brugnara, Laura Massella, Mark Joseph, Elena Levtchenko, Georges Deschênes, Jonathan Zonana, Zhongxin Yu, Jürgen Spranger, Marie Morimoto, Christy Mayfield, Andrew K. Gormley, Evelyne Lerut, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ICaR - Ischemia and repair, ICaR - Circulation and metabolism, and Pediatric surgery
Subjects: 0301 basic medicine, Male, Nephrotic Syndrome, pulmonary embolism, lcsh:Medicine, Fluorescent Antibody Technique, Pathogenesis, Focal segmental glomerulosclerosis, Glomerulosclerosis, Gene expression, Receptors, Genetics(clinical), Pharmacology (medical), Fluorescent Antibody Technique, Indirect, Child, Genetics (clinical), Medicine(all), Kidney, Receptors, Notch, Glomerulosclerosis, Focal Segmental, Wnt signaling pathway, General Medicine, 3. Good health, medicine.anatomical_structure, Drosophila melanogaster, Child, Preschool, Kidney Diseases, Indirect, Notch, Primary Immunodeficiency Diseases, Notch signaling pathway, Biology, Osteochondrodysplasias, Schimke immuno-osseous dysplasia, Focal Segmental, 03 medical and health sciences, medicine, Animals, Humans, Preschool, SMARCAL1 protein, arteriosclerosis, Research, lcsh:R, DNA Helicases, Immunologic Deficiency Syndromes, medicine.disease, Wnt Proteins, 030104 developmental biology, Dysplasia, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. Results We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. Conclusions We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0519-7) contains supplementary material, which is available to authorized users.
Published: 2016
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69. De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability

Author: Sébastien Schmitt, Amélie Piton, Christian P. Schaaf, Xenia Latypova, Brigitte Gilbert-Dussardier, Jill A. Rosenfeld, Kozo Tanaka, Robert Roger Lebel, Sylvie Odent, Haley Streff, Bertrand Isidor, Philippe Parent, Audrey Donnart, Sébastien Küry, Pierre Lindenbaum, Estelle Colin, Nodoka Chida, Masanori Ikeda, Marie Vincent, Alex Henderson, Thomas Besnard, Christian Dina, Dominique Bonneau, Eric Charpentier, Sally J. Davies, Yaping Yang, Anne Sophie Denommé, Benjamin Cogné, Stéphane Bézieau, Vani Jain, Richard Redon, Cédric Le Caignec, Sandra Mercier, Shelagh Joss, Annick Toutain, Kenji Iemura, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Baylor College of Medicine (BCM), Baylor University, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), University Hospital of Wales, SUNY Upstate Medical University, State University of New York (SUNY), Newcastle Upon Tyne Hospitals NHS Trust, Tohoku University [Sendai], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Contract grant sponsors: French Ministry of Health and Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107), Japanese Society of Promotion of Science, Ministry of Education Culture, Sports, Science and Technology of Japan, Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), The Japan Agency for Medical Research and Development, Takeda Science Foundation., Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), University Hospital of Wales (UHW), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Jonchère, Laurent
Subjects: 0301 basic medicine, Male, Microcephaly, Chromosomal Proteins, Non-Histone, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, POGZ, Microtubules, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Exome, microcephaly, Allele, Child, Gene, Genetics (clinical), Alleles, Sequence Deletion, Kinetochore, HP1, Chromosome, kinetochores, Facies, High-Throughput Nucleotide Sequencing, Syndrome, medicine.disease, Phosphoproteins, Chromatin, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Female, CHAMP1
Abstract: International audience; A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated non-consanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C\textgreaterG p.(Ser627*), c.1489C\textgreaterT; p.(Arg497*), c.1876\₁877delAG; p.(Ser626Leufs*4), c.1043G\textgreaterA; p.(Trp348*), c.1002G\textgreaterA; p.(Trp334*) and c.958\₉59delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders.
Published: 2015
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70. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Author: Patrick Niaudet, François Nobili, Guylhène Bourdat-Michel, Estelle Colin, Karin Dahan, Brigitte Gilbert-Dussardier, Claire Rigothier, Robert Novo, Dominique Martin-Coignard, Justine Bacchetta, Karim Bouchireb, Rémi Salomon, Thierry Hannedouche, Ariela Vergara-Jaque, Chantal Loirat, Dominique Chauveau, Pascal Houillier, Stéphane Burtey, Nicole Van Regemorter, Lamisse Mansour-Hendili, Sandrine Lemoine, Xavier Jeunemaitre, Muriel Holder-Espinasse, Michel Fischbach, Denis Morin, François-Guillaume Debray, S. Benoit, Valérie Leroy, Gilles Morin, Marie Alice Macher, Andreas Schleich, Mathilde Cailliez, Hassan Izzedine, Isabelle Roncelin, Gwenaëlle Roussey-Kesler, Cyrielle Treard, Claire Cartery, Hubert Nivet, Stéphane Lourdel, Véronique Baudouin, Pierre Cochat, Bertrand Knebelmann, Anne Blanchard, Wendy González, Estelle Desport, Tim Ulinski, Stella Dieguez, Marco Janner, Rosa Vargas-Poussou, Laurence Faivre, Alexandre Karras, Nelly Le Pottier, Francesco Emma, Philippe Vanhille, Renaud de la Faille, Anne Laure Sellier-Leclerc, J. Fourcade, Olivier Devuyst, Denis Fouque, Kenza Soulami, Aurélien Tiple, Etienne Bérard, Laurenne Dehoux, Marie Pierre Lavocat, Hélène François, Gérard Champion, Gerard Cardon, Georges Deschênes, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Univ Talca, Escuela Ingn Bioinfomat, Talca, Chile, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies rénales rares Néphrogones [CHU-HCL, Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice)-Fondation LENVAL-Hopital pour Enfants, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité de Néphrologie Pédiatrique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Division of Nephrology, Université catholique de Louvain Medical school, Université Catholique de Louvain = Catholic University of Louvain (UCL), Department of Nephrology and Urology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma]-IRCCS, Service de Néphrologie pédiatrique [Hôpital de Hautepierre, Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Human-machine spoken dialogue (CORDIAL), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Institut National de Recherche en Informatique et en Automatique (Inria)-École Nationale Supérieure des Sciences Appliquées et de Technologie (ENSSAT), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service de Physiologie [Georges-Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de Néphrologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de néphrologie adultes [CHU Necker], Sciences pour l'environnement (SPE), Centre National de la Recherche Scientifique (CNRS)-Université Pascal Paoli (UPP), Service de néphrologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Métal, Travaux et recherches archéologiques sur les cultures, les espaces et les sociétés (TRACES), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie, Hôpital de Clocheville, Service de néphrologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unité Néphrologie Pédiatrique [CHRU Lille], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Nephrology, Transplantation and Dialysis, Bordeaux, Hospices Civils de Lyon (HCL), Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd [Casablanca], CHU Clermont-Ferrand, Service de néphrologie et pédiatrie générale [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine interne et néphrologie, CH Valenciennes, Centre de Génétique de Bruxelles, Université libre de Bruxelles (ULB), Service de Génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Ministry of Health (Plan Maladies Rares), European Community FP7EUNEFRON 201590 and EURenOmics 2012‐305608, The Chilean PIA‐Conycit program (grant ACT‐1104), The Swiss National Science Foundation project (grant 310030_146490), RADIZ, Rare Diseases Initiative Zürich, a KFSP of the University of Zurich., Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Médecine interne et immunopathologie clinique [CHU Toulouse], Pôle IUCT [CHU Toulouse], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Université Pascal Paoli (UPP)-Centre National de la Recherche Scientifique (CNRS), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Université Catholique de Louvain (UCL), IRCCS-IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de nephrologie pédiatrique, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]-Sorbonne Université (SU), Free University of Brussels (BELGIUM), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Néphrologie, Centre Hospitalier Universitaire (CHU), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: Male, chloride channel, renal failure, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Dent Disease, ClC-5, medicine.disease_cause, Cohort Studies, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, low molecular weight proteinuria, Genetics (clinical), Genetics, Mice, Knockout, 0303 health sciences, Mutation, biology, MESH: Genetic Predisposition to Disease, MESH: Anion Transport Proteins, Phenotype, 3. Good health, Pedigree, Chloride Channels/chemistry/*genetics/metabolism, Dent Disease/*genetics/metabolism, Nephrocalcinosis, MESH: Bartter Syndrome, MESH: Mutation, Knockout, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Tubulopathy, Chloride Channels, medicine, Animals, Humans, Genetic Association Studies, 030304 developmental biology, MESH: Humans, CLCN5, MESH: Chloride Channels, Dent disease 1, medicine.disease, Bartter syndrome, biology.protein, OCRL, CLC family of chloride transporters and channels
Abstract: International audience; Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.
Published: 2015
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71. In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History

Author: A. Ziegler, L. Sentilhes, A. Guichet, D. Bonneau, P. Latour, F. Boussion, S. Triau, G. Piguet-Lacroix, M. Barth, D. Loisel, and Estelle Colin
Subjects: Pathology, medicine.medical_specialty, business.industry, Prenatal diagnosis, Disease, medicine.disease, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, In utero, 030225 pediatrics, Hydrops fetalis, Lysosomal storage disease, Medicine, Missense mutation, NPC1, Family history, business, 030217 neurology & neurosurgery
Abstract: Niemann–Pick type C (NPC) disease is a recessive disorder that results in unesterified cholesterol accumulating in the lysosomal and late endosomal system. It is caused by mutations in NPC1 or NPC2 genes and leads to systemic and neurodegenerative symptoms. Few cases of prenatal presentation of NPC have been reported and only two cases in the absence of previous family history, indicating the diagnosis is particularly difficult in such a situation. We report a prenatal diagnosis of NPC in a couple without family history. An ultrasound screening at 22 weeks of gestation (WG) detected fetal ascites and hepatomegaly, which were still present at 25, 27, and 29 WG, and a splenomegaly progressively appeared. No placentomegaly or other signs of hydrops fetalis were observed. The diagnostic of NPC was prenatally confirmed by a filipin test and NPC1 sequencing and multiplex ligation-dependent probe amplification assay which revealed a maternal missense mutation (c.2608T>C; p.Ser870Pro) and a paternal deletion of exons 5 to 25. This additional prenatal case of NPC suggests that even in the absence of family history, fetal ascites associated with splenomegaly but no hydrops should nonetheless arouse suspicion concerning this disease as a possible diagnosis.
Published: 2015

72. Dermatologic features of Smith-Magenis syndrome

Author: Dominique Bonneau M.D., Ludovic Martin, Morgane Guérin-Moreau, Estelle Colin, Hélène de Leersnyder, Sylvie Nguyen M.D., Joris Andrieux, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Hyperkeratosis, Scars, Folliculitis, Dermatology, Keratosis Pilaris, Skin Diseases, Diagnosis, Differential, Interviews as Topic, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Diagnosis, medicine, Humans, Trichomegaly, Keratoderma, Preschool, Child, Skin, 0303 health sciences, biology, integumentary system, business.industry, 030305 genetics & heredity, medicine.disease, biology.organism_classification, Smith–Magenis syndrome, 3. Good health, Pachydermia, Child, Preschool, Pediatrics, Perinatology and Child Health, Differential, Female, medicine.symptom, Smith-Magenis Syndrome, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Smith-Magenis syndrome (SMS) is characterized by distinctive facial and skeletal features, developmental delay, cognitive impairment, and behavioral abnormalities, including self-injurious behaviors. We aimed to investigate whether cutaneous features are common in SMS. We performed a complete skin examination in 20 young SMS patients. Skin features secondary to self-injurious behavior, such as bites, abrasions, dystrophic scars, limited spots of hyperkeratosis, anomalies of the nails, and whitlows, were found in the majority of patients. Acral pachydermia and fissured plantar keratoderma were common. Xerosis was constant and associated with extensive keratosis pilaris in the majority of patients. Dermatofibromas were frequent in older patients. The hair was dense and shiny, with an unusual hairline. Eyelash trichomegaly and heavy brows were common, as well as folliculitis on the back. The skin features of SMS have rarely been reported in the literature. Some of these are the consequence of neurobehavioral features, but some cutaneous features and abnormalities of appendages have not been reported in other related syndromes. Skin manifestations of SMS are varied, sometimes induced by self-injurious behavior and sometimes more specific. It remains to be determined whether the combination of the two kinds of signs could contribute to early diagnosis of the syndrome.
Published: 2015
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73. Variable Clinical Expression in Patients with Mosaicism for KCNQ2 Mutations

Author: Thomas Dailland, Gaetan Lesca, Nicole Philip, Estelle Colin, Ilias Tzelepis, Caroline Lacoste, Julie Sutera-Sardo, Affef Abidi, Anne Dieux Coeslier, Mathieu Milh, Pierre Cacciagli, Catherine Badens, Laurent Villard, Alexandra Afenjar, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jeanne de Flandre [Lille], Centre Hospitalier des Pays de Morlaix, Service de Génétique, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Villard, Laurent
Subjects: Male, Genetic counseling, DNA Mutational Analysis, Encephalopathy, Inheritance Patterns, Gene Expression, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, medicine.disease_cause, Severity of Illness Index, Epilepsy, Genetics, Humans, KCNQ2 Potassium Channel, Medicine, In patient, Gene, Genetics (clinical), Mutation, Mosaicism, business.industry, Infant, Newborn, Infant, Exons, medicine.disease, Phenotype, Epilepsy, Benign Neonatal, Aicardi Syndrome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, business, Spasms, Infantile
Abstract: International audience; Mutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity. Patients affected by benign familial neonatal epilepsy (BFNE) are at the milder end of the spectrum, they are affected by early onset epilepsy but their subsequent neurological development is usually normal. Mutations causing BFNE are often inherited from affected parents. Early infantile epileptic encephalopathy type 7 (EIEE7) is at the other end of the severity spectrum and, although EIEE7 patients have early onset epilepsy too, their neurological development is impaired and they will present motor and intellectual deficiency. EIEE7 mutations occur de novo. Electrophysiological experiments suggested a correlation between the type of mutation and the severity of the disease but intra and interfamilial heterogeneity exist. Here, we describe the identification of KCNQ2 mutation carriers who had children affected with a severe epileptic phenotype, and found that these individuals were mosaic for the KCNQ2 mutation. These findings have important consequences for genetic counseling and indicate that neurological development can be normal in the presence of somatic mosaicism for a KCNQ2 mutation.
Published: 2015
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74. Prenatal diagnosis of CHARGE syndrome by identification of a novel CHD7 mutation in a previously unaffected family

Author: Dominique Bonneau, Agnès Guichet, Estelle Colin, Stéphane Triau, B. Delorme, Alain Kitzis, Frédéric Bilan, Phillippe Gillard, and Françoise Boussion
Subjects: Pathology, medicine.medical_specialty, Mutation, business.industry, Heart malformation, Ocular Coloboma, Genital anomalies, Obstetrics and Gynecology, Prenatal diagnosis, Choanal atresia, medicine.disease, medicine.disease_cause, CHARGE syndrome, Chd7 gene, otorhinolaryngologic diseases, medicine, business, Genetics (clinical)
Abstract: CHARGE syndrome comprises ocular coloboma (C), heart malformation (H), choanal atresia (A), retardation of growth and/or anomalies of the central nervous system (R), genital anomalies (G) and ear anomalies (E). Prenatal diagnosis of CHARGE syndrome may be suspected in the presence of specific major anomalies at ultrasound examination. We describe prenatal diagnosis of CHARGE syndrome confirmed by identification of a mutation in CHD7 gene in a previously unaffected family. © 2012 John Wiley & Sons, Ltd.
Published: 2012
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75. Genetic background of Moyamoya syndrome: report of 3 new cases

Author: P. Van Bogaert, Marc Gibaud, M. Delion, J. Durigneux, Estelle Colin, and S. Gueden
Subjects: Pediatrics, Perinatology and Child Health, Neurology (clinical), General Medicine
Published: 2017
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76. Extensive Mongolian spots in 4p16.3 deletion (Wolf-Hirschhorn syndrome)

Author: Dominique Bonneau, Thierry Levade, Magalie Barth, Estelle Colin, Alban Ziegler, Lucille Pinson, and Agnès Guichet
Subjects: Genetics, business.industry, Wolf-Hirschhorn Syndrome, Developmental Disabilities, Infant, General Medicine, medicine.disease, Pathology and Forensic Medicine, Mongolian Spot, Pediatrics, Perinatology and Child Health, Medicine, Humans, Female, Anatomy, Chromosome Deletion, Chromosomes, Human, Pair 4, business, Child, Mongolian spots, Wolf–Hirschhorn syndrome, Genetics (clinical)
Published: 2014

77. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Author: Valérie Desquiret-Dumas, Patrizia Amati-Bonneau, Magalie Barth, Marlène Rio, Arnaud Chevrollier, Guy Lenaers, Florine Oca, Naïg Gueguen, Abdelhamid Slama, Pascal Reynier, Vincent Procaccio, Xavier Zanlonghi, Marta Momtchilova, Diana Rodriguez, Estelle Colin, Christine Barnerias, Dominique Bonneau, Marc Ferré, Sylvie Nguyen, Isabelle Desguerre, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Clinique Sourdille, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Éloi [Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Genetics, 0303 health sciences, Ataxia, [SDV]Life Sciences [q-bio], Biology, medicine.disease, Compound heterozygosity, eye diseases, 3. Good health, Optic neuropathy, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Mitochondrial myopathy, medicine, Behr syndrome, Optic Atrophy 1, Neurology (clinical), medicine.symptom, Chronic progressive external ophthalmoplegia, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Sir, The Behr syndrome (MIM#210000) is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay (Behr, 1909). Although the disorder is believed to be inherited in an autosomal recessive manner, it may be clinically heterogeneous, encompassing several genetic aetiologies and patterns of inheritance. Recently, an adult-onset Behr-like syndrome, including optic atrophy and ataxia, was reported in two brothers carrying a heterozygous mutation in the optic atrophy type 1 gene ( OPA1 , p.Cys551Tyr) (Marelli et al. , 2011). Heterozygous mutations in OPA1 , a gene encoding for a dynamin-related GTPase involved in mitochondrial dynamics and mtDNA maintenance, are the main causes of autosomal dominant optic atrophy (DOA). In DOA, the optic neuropathy occurs insidiously in the first decade of life leading to various levels of visual impairment. As many as 20% of patients with DOA exhibit extra-ocular neuromuscular signs including deafness (Amati-Bonneau et al., 2005), chronic progressive external ophthalmoplegia, ataxia, peripheral neuropathy and mitochondrial myopathy with multiple mtDNA deletions, also called the ‘DOA plus’ phenotype (Amati-Bonneau et al. , 2008; Yu-Wai-Man et al. , 2010). The ‘DOA plus’ phenotype, which is similar to that observed in multi-systemic mitochondrial disorders (Amati-Bonneau et al. , 2005), is often associated with missense mutations in OPA1 (Yu-Wai-Man et al. , 2010). Apart from these autosomal dominant forms, only a few syndromic cases have so far been reported with compound heterozygous OPA1 mutations suggestive of either recessive or semi-dominant patterns of inheritance (Pesch et al. , 2001; Yu-Wai-Man et al. , 2010; Schaaf et al. , 2011). However, the clinical spectrum of these emerging double-mutant OPA1 -related disorders remains to be characterized. We here report four cases of children affected by the Behr syndrome associated with compound heterozygous OPA1 mutations. This …
Published: 2014

78. Fetal intracerebral hemorrhage and cataract: think COL4A1

Author: A. Guichet, M Mine, Dominique Bonneau, E Tournier-Lasserve, C Ploton, B. Delorme, F. Boussion, Estelle Colin, L. Sentilhes, and A Sarfati
Subjects: Adult, Collagen Type IV, Pathology, medicine.medical_specialty, medicine.disease_cause, Cataract, Ultrasonography, Prenatal, Type IV collagen, Pregnancy, Cerebral microangiopathy, medicine, Humans, cardiovascular diseases, Cerebral Hemorrhage, Intracerebral hemorrhage, Fetus, Mutation, business.industry, Familial Porencephaly, Obstetrics and Gynecology, medicine.disease, Prenatal onset, nervous system diseases, Fetal Diseases, Pediatrics, Perinatology and Child Health, Female, business
Abstract: The COL4A1 gene encodes the alpha1 chain of type IV collagen, a crucial component of nearly all basement membranes. Mutations in COL4A1 were first associated with cerebral microangiopathy and familial porencephaly. Recently, several authors have reported mutations in COL4A1 as a Mendelian cause of prenatal onset intracranial hemorrhage (ICH). We report two cases of prenatal ICH associated with cataract and suggest that COL4A1 mutation should be envisaged in fetuses with prenatal ICH, especially in the presence of lens abnormalities at ultrasound examination.
Published: 2013

79. Auteurs

Author: Françoise Boussion, Philippe Pézard, Jean-Philippe Bault, Estelle Colin, Agnès Guichet, and Jean-Marc Levaillant
Published: 2013
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80. Sensorineural hearing loss in OPA1-linked disorders

Author: Guy Lenaers, Pascal Reynier, Martine Crochet, Stéphanie Leruez, Sabine Defoort-Dhellemmes, Marc Ferré, Gitte Juul, Dominique Bonneau, Catherine Blanchet, Christian P. Hamel, Julie Lamblin, Vincent Procaccio, Estelle Colin, Christophe Verny, Valérie Drouin, Dan Milea, Michael Larsen, Patrizia Amati-Bonneau, Catherine Vincent-Delorme, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), University of Copenhagen = Københavns Universitet (KU), CHU Lille, Université de Lille, CHU Rouen, Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH), Institut des Neurosciences de Montpellier (INM), and Univ Angers, Okina
Subjects: Male, medicine.medical_specialty, Hearing loss, [SDV]Life Sciences [q-bio], Otoacoustic emission, Audiology, GTP Phosphohydrolases, 03 medical and health sciences, 0302 clinical medicine, Bone conduction, Atrophy, Central Nervous System Diseases, Optic Atrophy, Autosomal Dominant, Medicine, Humans, Letters to the Editor, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, business.industry, medicine.disease, eye diseases, [SDV] Life Sciences [q-bio], Mutation (genetic algorithm), 030221 ophthalmology & optometry, Medical genetics, Sensorineural hearing loss, Female, Neurology (clinical), Audiometry, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: ARTICLE Sir, We have read with interest the article by Yu-Wai-Man et al. (2010) reporting heterogeneous multi-system manifestations in 104 patients affected with autosomal dominant optic atrophy (DOA) caused by mutations in the nuclear gene encoding the mitochondrial OPA1 protein. Yu-Wai-Man et al. (2010) found that ∼20% of the OPA1 mutation carriers had complicated forms of dominant optic atrophy, the so-called ‘DOA+’ forms, associating extra-ocular features such as hearing loss or neuromuscular disorders similar to those observed in mitochondrial oxidative phosphorylation defects or in syndromes with mitochondrial DNA instability (Amati-Bonneau et al. , 2008; Hudson et al. , 2008; Yu-Wai-Man et al. , 2010). Interestingly, Yu-Wai-Man et al. (2010) report that sensorineural hearing loss, the most frequent extra-ocular manifestation in ‘DOA+’, occurred in nearly two-thirds of their patients. To characterize the prevalence and the type of hearing loss in OPA1 mutation carriers, we retrospectively reviewed the files of 1380 patients affected with hereditary optic neuropathies referred to our laboratory from 2003 to 2011 for molecular diagnosis. During this period, an OPA1 mutation was identified in 327 patients (24%), 21 of whom (6.4%) had hearing impairment. Clinical information about these 21 patients was obtained from 13 departments of ophthalmology, ENT and medical genetics (12 in France, one in Denmark) (Table 1). All patients had undergone standard pure-tone air and bone conduction audiometry (125–8000 Hz), and speech audiometry had been performed in eight patients. Results of auditory brainstem responses and otoacoustic emission testing were available for only eight patients (Table 2). View this table: Table 1 Clinical and molecular findings in 21 OPA1 mutation carriers affected with optic atrophy and hearing loss View this table: Table 2 Audiological data from 10 OPA1 mutation carriers The 21 OPA1 mutation carriers with hearing loss (11 females and 10 males) belonged to 13 families and were aged from 12 to 73 years …
Published: 2013
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81. Binder phenotype in mothers affected with auto-immune disorders

Author: A. Mercier, Renaud Touraine, Dominique Bonneau, J. Levaillant, M. Gerard-Blanluet, M. Ferry, Sylvie Odent, Estelle Colin, Laurent Pasquier, Agnès Guichet, Magalie Barth, Françoise Boussion, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU Saint-Etienne-Hôpital nord, Service de radiologie et imagerie [Béclère], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Service de gynécologie-obstétrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], CHU Pontchaillou [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De Villemeur, Hervé, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Adult, Male, Pathology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Mothers, Early pregnancy factor, Nose, Autoimmune Diseases, 03 medical and health sciences, Pregnancy, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Maxilla, medicine, Humans, Chondrodysplasia punctata, [SDV.BDD]Life Sciences [q-bio]/Development Biology, reproductive and urinary physiology, Ultrasonography, 030304 developmental biology, 0303 health sciences, biology, business.industry, 030305 genetics & heredity, Infant, Newborn, Obstetrics and Gynecology, medicine.disease, Maternal autoimmune disease, Phenotype, Hypoplasia, Maxillofacial Abnormalities, 3. Good health, Pregnancy Complications, Pediatrics, Perinatology and Child Health, embryonic structures, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business
Abstract: International audience; Abstract Objective: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. Patients and Methods: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. Results: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. Conclusion: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes.
Published: 2011
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82. Mutation screening of the EYA1, SIX1 and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations

Author: Dominique Bonneau, Corinne Antignac, Pauline Krug, Valérie Koubi, Rémi Salomon, Laurence Heidet, Estelle Colin, Vincent Morinière, Heinz D. Gabriel, Sandrine Marlin, Service de néphrologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], AP-HP, Service de Génétique, Centre de Référence des Surdités Congénitales et Héréditaires, Hôpital Trousseau, Diagenos, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), AP-HP Centre de référence des maladies rénales héréditaires de l'enfant et de l'adulte, Université Paris Descartes - Paris 5 (UPD5), Service de Néphrologie Pédiatrique, AP-HP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université d'Angers ( UA ) -CHU Angers, and Université Paris Descartes - Paris 5 ( UPD5 )
Subjects: Male, Mutation rate, DNA Mutational Analysis, Biology, medicine.disease_cause, Bioinformatics, Cohort Studies, 03 medical and health sciences, Exon, Genotype-phenotype distinction, Genetics, medicine, Missense mutation, Humans, Gene, Genetics (clinical), 030304 developmental biology, Branchio-oto-renal syndrome, Homeodomain Proteins, 0303 health sciences, Mutation, 030305 genetics & heredity, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Life Sciences, medicine.disease, Phenotype, 3. Good health, Female, Protein Tyrosine Phosphatases, Branchio-Oto-Renal Syndrome
Abstract: International audience; Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described 4 missense mutations in SIX5 in 5 unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations and one change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.
Published: 2011
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83. Kif7 Mutations Cause Fetal Hydrolethalus And Acrocallosal Syndromes

Author: Marie Hélène Saint Frison, Sophie Patrier, Elif Uz, Gülen Eda Utine, Valérie Cormier-Daire, Nicolas Goudin, Nadia Elkhartoufi, Gönöl Ogur, Nurten A. Akarsu, Stanislas Lyonnet, Daniela Buzas, Koray Boduroğlu, Mark Winey, Tania Attié-Bitach, L. Fertitta, Karlien L.M. Coene, Sophie Thomas, Christine Bole-Feysot, Christopher L. Bennett, Raoul C.M. Hennekam, Arnold Munnich, Philip L. Beales, Nicholas Katsanis, Marie Gonzales, Luc Rigonnot, Patrick Nitschke, Estelle Colin, Christel Thauvin-Robinet, Yasemin Alanay, Alain Schmitt, Michel Vekemans, Solenn Pruvost, Férechté Encha-Razavi, Jean Pierre Siffroi, Nicolas Cagnard, Erica E. Davis, Céline Gomes, N. Joye, Audrey Putoux, Çocuk Sağlığı ve Hastalıkları, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and OMÜ
Subjects: Heart Defects, Congenital, Male, medicine.medical_specialty, animal structures, Adolescent, Acrocallosal Syndrome, Hydrolethalus syndrome, Kinesins, Biology, medicine.disease_cause, Ciliopathies, Article, Cerebral Ventricles, Consanguinity, Internal medicine, GLI3, Genetics, medicine, Humans, Hedgehog Proteins, Cilia, Child, Genetics & Heredity, Mutation, Cilium, Infant, Acrocallosal syndrome, medicine.disease, Magnetic Resonance Imaging, Hedgehog signaling pathway, Pedigree, Ciliopathy, Endocrinology, Child, Preschool, Female, Hand Deformities, Congenital, Hydrocephalus
Abstract: Coene, Karlien/0000-0001-9873-1458; Alanay, Yasemin/0000-0003-0683-9731; THOMAS, Sophie/0000-0002-8569-3277; Lyonnet, Stanislas/0000-0001-5426-9417; Akarsu, Nurten/0000-0001-5432-0032; ATTIE-BITACH, Tania/0000-0002-1155-3626; Davis, Erica/0000-0002-2412-8397; Boduroglu, Koray/0000-0001-6260-1942; Cagnard, Nicolas/0000-0002-9051-1896; cormier-daire, valerie/0000-0002-2839-9856; Katsanis, Nicholas/0000-0002-2480-0171; PUTOUX, Audrey/0000-0001-5496-4604 WOS: 000291017000021 PubMed: 21552264 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. ANRFrench National Research Agency (ANR) [07-MRAR-010-02, BLAN-1122-01]; E-RARE [07-ERare-001-01]; Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S420]; US National Institutes of Health from the National Institute of Child Health and Development [R01HD04260]; National Institute of Diabetes, Digestive and Kidney DisordersUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK072301]; Academie de Medecine; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS039818-07]; Huygens Scholarship Programme; Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [NWO Toptalent-021.001.014]; March of Dimes FoundationMarch of Dimes [1-FY07-422]; Medical Research CouncilMedical Research Council UK (MRC) [G0801843] We are grateful to families and to the French Society of Fetal Pathology (SOFFOET) for participating in the study, to C. Dubourg, P. Wieacker, B. Leroy, N. Laurent, V. Fermeaux, S. Odent for fetuses' referral and to A. Schinzel and A. David for ACLS samples. We thank M. Zarhrate, A. Aguilar, N. Spasky and L. Besse for technical help. We thank N. Boddaert for helpful discussion. This work was supported by grants from ANR (FETALCILIOPATHIES number 07-MRAR-010-02 and FOETOCILPATH number BLAN-1122-01), E-RARE (Cranirare number 07-ERare-001-01) the Scientific and Technological Research Council of Turkey (TUBITAK, grant number 108S420 to N. A. A.), the US National Institutes of Health grant R01HD04260 from the National Institute of Child Health and Development (N. K.), R01DK072301 from the National Institute of Diabetes, Digestive and Kidney Disorders (N. K.) and the European Union (EU-SYSCILIA; E. E. D., N. K. and P. L. B.). A. P. was granted a fellowship from the Academie de Medecine. S. T. is supported by NIH 'Hereditary Basis of Neural Tube Defects' No NS039818-07 to M. Speer. K. L. M. C. is supported by the Huygens Scholarship Programme and the Netherlands Organization for Scientific Research (NWO Toptalent-021.001.014). M. W. was a fellow of the Guggenheim Foundation and was supported by the March of Dimes Foundation (1-FY07-422). P. L. B. is a Wellcome Trust Senior Research Fellow. N. K. is a Distinguished George W. Brumley Professor.
Published: 2011

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83 results on '"Estelle Colin"'

51. Duplication of 10q24 locus: broadening the clinical and radiological spectrum

52. A new case of pcsk1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review

53. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

54. Karyotype is not dead (yet)!

55. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

56. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

57. Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

58. Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia

59. Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

60. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

61. Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature

62. Hematopoietic stem cell transplantation in 29 patientshemizygous for hypomorphic IKBKG/NEMO mutations

63. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

64. SLC24A5 Mutations Are Associated with Non-Syndromic Oculocutaneous Albinism

65. Mutations inWNT10Aare frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

66. Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin α

67. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

68. Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

69. De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability

70. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

71. In Utero Diagnosis of Niemann-Pick Type C in the Absence of Family History

72. Dermatologic features of Smith-Magenis syndrome

73. Variable Clinical Expression in Patients with Mosaicism for KCNQ2 Mutations

74. Prenatal diagnosis of CHARGE syndrome by identification of a novel CHD7 mutation in a previously unaffected family

75. Genetic background of Moyamoya syndrome: report of 3 new cases

76. Extensive Mongolian spots in 4p16.3 deletion (Wolf-Hirschhorn syndrome)

77. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

78. Fetal intracerebral hemorrhage and cataract: think COL4A1

79. Auteurs

80. Sensorineural hearing loss in OPA1-linked disorders

81. Binder phenotype in mothers affected with auto-immune disorders

82. Mutation screening of the EYA1, SIX1 and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations

83. Kif7 Mutations Cause Fetal Hydrolethalus And Acrocallosal Syndromes

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83 results on '"Estelle Colin"'

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