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14 results on '"Kay D. MacDermot"'

1. Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder

Author

Dianne F. Newbury, Alessandra Renieri, Roberto Canitano, Anthony P. Monaco, Francesca Mari, Jenny C. Taylor, Kay D. MacDermot, Elham Sadighi Akha, Simon E. Fisher, and Samantha J. L. Knight

Subjects
Neuroinformatics, Letter, Apraxias, Biology, 03 medical and health sciences, Genetics, Pervasive developmental disorder, medicine, Humans, Copy-number variation, Child, Genetics (clinical), 030304 developmental biology, Sequence Deletion, 0303 health sciences, Comparative Genomic Hybridization, 030305 genetics & heredity, Genetic data, Forkhead Transcription Factors, Syndrome, Microdeletion syndrome, medicine.disease, Pedigree, Childhood apraxia of speech, Chromosomes, Human, Pair 16
Abstract

We report clinical findings that extend the phenotype of the ~550 kb 16p11.2 microdeletion syndrome to include a rare, severe, and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech (CAS). CAS is the speech disorder identified in a multigenerational pedigree ('KE') in which half of the members have a mutation in FOXP2 that co-segregates with CAS, oromotor apraxia, and low scores on a nonword repetition task. Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive, language, speech, oral mechanism, motor, and developmental histories and performance. Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS. Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient. These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research. We discuss implications of findings for issues in both literatures.

Published
2013

2. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia

Author

Yanick J. Crow, Gwendoline Pfennig, Miranda Splitt, David Geneviève, Elisabeth Flori, Carine Le Goff, Valérie Drouin-Garraud, Deborah Krakow, Andrea Superti-Furga, Jane A. Hurst, Koenraad Devriendt, Clémentine Mahaut, Sally Ann Lynch, Sahar Mansour, Arnold Munnich, Isabelle Pressac-Diebold, Sheila Unger, Nathalie Dagoneau, Martine Le Merrer, Klaske D Lichtenbelt, Denise Williams, Raoul C.M. Hennekam, Heloísa G. dos Santos, Kay D. MacDermot, Angela F. Brady, Valérie Cormier-Daire, André Mégarbané, Stanislas Lyonnet, Slimane Allali, Yasemin Alanay, University of Groningen, 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), Ankara University School of Medicine [Turkey], North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Genetic Medicine, University of Manchester, Manchester Academic Heath Science Centre, Department of Medical Genetics, Leuven University Hospital, Leuven, Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of genetics, Strasbourg hospital, Strasbourg, Service de Génétique Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics, Academic Medical Center, University of Amsterdam, Departement of Clinical Genetics, Oxford Radcliffe Hospitals, Cedars-Sinai Medical Center, University Medical Center [Utrecht], National Center for Medical Genetics, Dublin, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Université Saint-Joseph de Beyrouth (USJ), Department of Medical Genetics , Lisboa, Institute of Human Genetics, Newcastle, Department of Pediatrics, Centre Hospitalier Universitaire, Vaudois, Lausanne, Birmingham women's hospital, Birmingham, Peer, Hal, SW Thames Regional Genetics Service, St George’s University of London, London, Unité de génétique médicale, Université Saint Joseph, Beyrouth, 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 ), Genetics Unit, Department of Pediatrics Hacettepe, University School of Medicine, Ankara, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Cedars Sinai Medical Center, Los Angeles, Department of Medical Genetics, University Medical Center, Utrecht, Université Saint-Joseph de Beyrouth ( USJ ), Çocuk Sağlığı ve Hastalıkları, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and Faculteit der Geneeskunde

Subjects
Male, Pathology, WEILL-MARCHESANI-SYNDROME, ACROMICRIC DYSPLASIA, Japan, Acromicric dysplasia, Eye Abnormalities, Child, Genetics (clinical), Genetics, Inclusion Bodies, Genetics & Heredity, 0303 health sciences, Extracellular Matrix Proteins, 030305 genetics & heredity, Weill–Marchesani syndrome, 3. Good health, Pedigree, Europe, Connective Tissue, Child, Preschool, Medical genetics, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Ear infection, Limb Deformities, Congenital, Dwarfism, Biology, Short stature, Article, 03 medical and health sciences, Genetic Heterogeneity, Middle East, Molecular genetics, medicine, Humans, Clinical genetics, Connective tissue disease, 030304 developmental biology, Bone Diseases, Developmental, Genetic heterogeneity, MUTATIONS, Infant, medicine.disease, Dysplasia, Mutation, Skin Abnormalities
Abstract

Background Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). Methods Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). Results The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. Conclusions It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Published
2011
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3. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients

Author

Alison Kerr, Kay D. MacDermot, Yanick J. Crow, David Neil Cooper, Rachel Butler, Angus John Clarke, Peter Huppke, J. Horn, G. Hermon, Sharon D. Whatley, Franco Laccone, Alex Magee, Willie Reardon, David Ravine, David J. Bunyan, A. Donaldson, E. Sweeney, Bronwyn Kerr, R. A. Smith, Julie Evans, Daniela T. Pilz, Stephen Davies, Hayley Archer, L. P. Lazarou, Julian R. Sampson, and Z. Miedzybrodzka

Subjects
Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Adolescent, Methyl-CpG-Binding Protein 2, DNA Mutational Analysis, Gene Dosage, Rett syndrome, Biology, Gene dosage, MECP2, Cohort Studies, Molecular genetics, Rett Syndrome, Genetics, medicine, Humans, Atypical Rett syndrome, Genetic Testing, Multiplex ligation-dependent probe amplification, Child, Genetics (clinical), Chromosome Aberrations, Breakpoint, Gene rearrangement, medicine.disease, Child, Preschool, Female, Letter to JMG
Abstract

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Published
2005
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4. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

Author

Anne De Paepe, Kay D. MacDermot, Eva-Lena Stattin, Constance T.R.M. Schrander-Stumpel, Bert Callewaert, Maryse Bonduelle, Paul Coucke, Julie De Backer, Machteld Baetens, Bart Loeys, I.M. Gaspar, Marjolijn Renard, Jean Pierre Fryns, Diogo Cavaco, Harry C. Dietz, Laurence Campens, Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction

Subjects
Marfan syndrome, Male, Pathology, Cohort Studies, Aortic aneurysm, Transforming Growth Factor beta, Medicine and Health Sciences, Smooth muscle alpha-actin, Aged, 80 and over, biology, Middle Aged, Phenotype, MARFAN-SYNDROME, Pedigree, Up-Regulation, cardiovascular system, Female, ACTA2, Cardiology and Cardiovascular Medicine, Signal Transduction, Adult, medicine.medical_specialty, THORACIC AORTIC-ANEURYSMS, Adolescent, FIBRONECTIN, TGF beta signaling, Thoracic aortic aneurysm, Article, DISSECTIONS, ACTIN, TGF beta signaling pathway, medicine, MYH11, LOCUS, EXTRACELLULAR-MATRIX, Humans, Aged, Aortic Aneurysm, Thoracic, Myosin Heavy Chains, RECEPTOR, business.industry, Myosin heavy chain 11, Transforming growth factor beta, medicine.disease, Actins, Aortic Dissection, Mutation, biology.protein, Human medicine, business
Abstract

Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGF beta) signaling (TGF beta receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). Methods and result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGF beta signaling pathway. Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGF beta signaling. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Published
2013

5. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], 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), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, 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)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, 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), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011
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6. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Peter Vollenweider, Leena Peltonen, Audrey Labalme, Jessica L. Buxton, Alessandra Ferrarini, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Marie Pigeyre, Sébastien Jacquemont, Vincent Mooser, Audrey Guilmatre, C. Lecoeur, Muriel Holder-Espinasse, Bettina Blaumeiser, Elena G. Bochukova, Ni Huang, Andrew Walley, Danielle Martinet, Peter Jacobson, B. Leheup, Marie-Pierre Lemaitre, A. Brioschi, Julia M. Keogh, Damien Sanlaville, Stephen O'Rahilly, Robert Sladek, Bruno Delobel, Fanny Stutzmann, Sophie Dupuis-Girod, Philippe Froguel, Muriel Gaillard, Anne Philippe, Katrin Männik, Jean-Marie Cuisset, M. Béri-Dexheimer, Lachlan J. M. Coin, Fei Chen, François Pattou, Katrin Õunap, Mari Nelis, A.-L. Hartikainen, Jean-Claude Chèvre, Philippe Jonveaux, Alice Goldenberg, Kay D. MacDermot, Elana Henning, Odile Boute, Sonia Bouquillon, Armand Valsesia, Valérie Malan, Stéphane Lobbens, R. F. Kooy, Alexandra I. F. Blakemore, Marie-Pierre Cordier, Lena M. S. Carlsson, Marjo-Riitta Järvelin, Lars Sjöström, Paul Elliott, C Le Caignec, Florence Fellmann, Nadège Calmels, Dominique Campion, M. M. van Haelst, Vincent Vatin, B. Balkau, Jacques S. Beckmann, Mark I. McCarthy, Robert Caiazzo, Jean-Louis Mandel, Joris Andrieux, Nouchine Hadjikhani, Catherine Vincent-Delorme, David Meyre, Ants Kurg, J. S. El-Sayed Moustafa, Johanna C. Andersson, Jean Chiesa, Michèle Mathieu-Dramard, R. Touraine, Tõnu Esko, Albert David, Alexandre Reymond, Priit Palta, Ghislaine Plessis, Andres Metspalu, Robin G. Walters, Vittorio Giusti, Richard J. Ellis, Bertrand Isidor, Anne-Emmanuelle Ambresin, A J de Smith, I. S. Farooqi, Matthew E. Hurles, Mario Falchi, Medical Research Council (MRC), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments

Subjects
Male, Aging, SAMPLE, Inheritance Patterns, Genome-wide association study, Penetrance, MC4R, Body Mass Index, Cohort Studies, 0302 clinical medicine, SH2B1, Missing heritability problem, Age of Onset, Child, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, Sex Characteristics, Multidisciplinary, Mental-Retardation, Adolescent Adult Age of Onset Aging Body Mass Index Case-Control Studies Child *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cognition Disorders/complications/genetics Cohort Studies Europe Female Genome-Wide Association Study Heterozygote Humans Inheritance Patterns/genetics Male Mutation/genetics Obesity/complications/*genetics/*physiopathology *Penetrance Reproducibility of Results Sex Characteristics Young Adult, 3. Good health, Multidisciplinary Sciences, Europe, Adolescent, Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Mutation/genetics, Obesity/complications, Obesity/genetics, Obesity/physiopathology, Reproducibility of Results, Young Adult, Medical genetics, Science & Technology - Other Topics, CHILDHOOD OBESITY, medicine.medical_specialty, Childhood Obesity, BIRTH, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, Article, Childhood obesity, 03 medical and health sciences, medicine, MICRODELETION, Obesity, GENOME-WIDE ASSOCIATION, AUTISM, education, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, MULTIDISCIPLINARY SCIENCES, FRAMESHIFT MUTATION, Individuals, medicine.disease, RISK LOCI, INDIVIDUALS, CIRCULAR BINARY SEGMENTATION, Mutation, Human medicine, Cognition Disorders, MENTAL-RETARDATION, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16
Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Published
2010
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7. Nicolaides-Baraitser Syndrome: Delineation of the Phenotype

Author

Emma Wakeling, Elizabeth C. Rosser, Sérgio B. Sousa, Alma Kuechler, Dragana Josifova, Denise Horn, Alain Verloes, Nora Shannon, Raoul C.M. Hennekam, Valérie Cormier-Daire, Armand Bottani, Alan Fryer, Irene Stolte-Dijkstra, Omar A. Abdul-Rahman, Louise C. Wilson, Gabriele Gillessen-Kaesbach, Melissa Lees, Alex Magee, Fanny Morice-Picard, Ajoy Sarkar, Kay D. MacDermot, Amsterdam Neuroscience, Amsterdam Public Health, and Paediatric Genetics

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, etiology, growth retardation, Short stature, mental retardation, Young Adult, Genetics, medicine, Humans, Abnormalities, Multiple, Coffin-Siris syndrome, Child, Coffin–Siris syndrome, Genetics (clinical), seizures, SPARSE HAIR, business.industry, Brachydactyly, Nicolaides-Baraitser syndrome, Infant, Newborn, Infant, Dysostosis, Syndrome, medicine.disease, Dermatology, Radiography, Developmental disorder, Phenotype, Nicolaides–Baraitser syndrome, natural history, Child, Preschool, Disease Progression, Etiology, Female, medicine.symptom, Differential diagnosis, business, MENTAL-RETARDATION, Follow-Up Studies
Abstract

Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data of the earlier reported patients. A detailed comparison of the 23 patients is provided. NBS is a distinct and recognizable entity, and probably has been underdiagnosed until now. Main clinical features are severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time. The main differential diagnosis is Coffin-Siris syndrome. There is no important gender difference in occurrence and frequency of the syndrome, and all cases have been sporadic thus far. Microarray analysis performed in 14 of the patients gave normal results. Except for the progressive nature there are no clues to the cause. (C) 2009 Wiley-Liss, Inc.

Published
2009

8. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits

Author

Robert L. Smith, Elena Bonora, Fiona Haslam McKenzie, Kay D. MacDermot, Anne Marie Coupe, Sonja C. Vernes, Simon E. Fisher, Nuala Sykes, Cecilia S. L. Lai, Faraneh Vargha-Khadem, Anthony P. Monaco, Macdermot, Kay D., Bonora, Elena, Sykes, Nuala, Coupe, Anne-Marie, Lai, Cecilia S. L., Vernes, Sonja C., Vargha-Khadem, Faraneh, Mckenzie, Fiona, Smith, Robert L., Monaco, Anthony P., and Fisher, Simon E.

Subjects
Heterozygote, Nonsense mutation, DNA Mutational Analysis, Molecular Sequence Data, Codon, Initiator, Mothers, Biology, Specific language impairment, Speech Disorders, 03 medical and health sciences, 0302 clinical medicine, Genetic, Communication disorder, Sequence Homology, Nucleic Acid, Report, Genetics, medicine, Humans, Protein Isoforms, Genetics(clinical), Language disorder, Amino Acid Sequence, Developmental verbal dyspraxia, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Language Disorders, Base Sequence, Sequence Homology, Amino Acid, Siblings, Dyslexia, Genetic Variation, FOXP2, Forkhead Transcription Factors, Exons, Sequence Analysis, DNA, medicine.disease, KE family, Pedigree, Protein Structure, Tertiary, Alternative Splicing, Codon, Nonsense, Codon, Terminator, 030217 neurology & neurosurgery, Transcription Factors
Abstract

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition. © 2005 by The American Society of Human Genetics. All rights reserved.

Published
2005

9. Neuropathic pain in Anderson-Fabry disease: pathology and therapeutic options

Author

John MacDermot and Kay D MacDermot

Subjects
Pharmacology, medicine.medical_specialty, Clinical Trials as Topic, Vascular disease, business.industry, Genetic enhancement, Mononeuropathies, Pain, Enzyme replacement therapy, Disease, Fabry's disease, medicine.disease, Fabry disease, Surgery, Polyneuropathies, Peripheral neuropathy, Neuropathic pain, medicine, Fabry Disease, Humans, Intensive care medicine, business
Abstract

An inherited deficiency of the enzyme alpha-galactosidase A is manifest clinically as Anderson-Fabry disease. Most affected patients present with severe peripheral pain in childhood or early adult life, and frequently progress to multi-organ failure by the 4th or 5th decades. The present review examines the probable mechanisms that contribute to pain in these patients, and outlines some of the treatment options that are currently used. The successful outcome of the first two trials of enzyme replacement therapy suggest that this disease might be amenable in the future to gene therapy.

Published
2001

10. Apparent normalisation of fetal renal size in autosomal dominant polycystic kidney disease (PKD1)

Author

Demetrios L Economides, A K Saggar-Malik, Sally E Blackmore, Kay D MacDermot, and Steve Jeffery

Subjects
medicine.medical_specialty, Pathology, Heterozygote, Autosomal dominant polycystic kidney disease, Prenatal diagnosis, urologic and male genital diseases, Kidney, Pregnancy, Internal medicine, Prenatal Diagnosis, Genetics, medicine, Humans, Cyst, Genetics (clinical), Ultrasonography, Fetus, PKD1, urogenital system, business.industry, medicine.disease, Polycystic Kidney, Autosomal Dominant, medicine.anatomical_structure, Endocrinology, embryonic structures, Gestation, Female, business, Kidney disease, Follow-Up Studies
Abstract

We present a family with adult onset autosomal dominant polycystic kidney disease (ADPKD) in two generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23 and 34 weeks of gestation. Surprisingly, the newborn renal scan showed normal sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in one kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs. The observed normalisation of fetal renal ultrasound appearances at birth has not previously been described in fetuses presenting with PKD1.

Published
1998

11. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome

Author

Alex Magee, Alma Kuechler, Livia Garavelli, Nora Shannon, Simone Gana, Fanny Morice-Picard, Elizabeth C. Rosser, Koenraad Devriendt, Joris Vermeesch, Isabel Filges, Patrick Van Dijck, Danny Huylebroeck, Małgorzata Krajewska-Walasek, Alejandro Sifrim, Stella A. de Man, Valérie Cormier-Daire, Yves Moreau, Antoine H. C. van Kampen, Marie José H. Van Den Boogaard, Catheline Vilain, Shane McKee, Ewa Obersztyn, Alan Fryer, Louise C. Wilson, Sérgio B. Sousa, Jacek Pilch, Saskia M. Maas, Orsetta Zuffardi, Raoul C.M. Hennekam, Bryan D. Hall, Dagmar Wieczorek, Annick Vogels, Kay D. MacDermot, Marco Castori, Eve Seuntjens, Jakub Klapecki, Denise Horn, Jean Pierre Fryns, Beata Nowakowska, Gabriele Gillessen-Kaesbach, Barbera D. C. van Schaik, Nelson Avonce, Matthew A. Deardorff, Armand Bottani, Irene Stolte-Dijkstra, Matthew A. Lines, Omar A. Abdul-Rahman, Jeroen Van Houdt, Emma Wakeling, Clinical Genetics, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, CCA -Cancer Center Amsterdam, Epidemiology and Data Science, Human Genetics, Paediatric Genetics, APH - Amsterdam Public Health, and Paediatrics

Subjects
Adult, Male, Nonsynonymous substitution, EXPRESSION, Adolescent, Foot Deformities, Congenital, Transcription, Genetic, SEQUENCING DATA, Chromosomal Proteins, Non-Histone, ATPase, Molecular Sequence Data, Mutation, Missense, Medizin, VARIANTS, Hypotrichosis, Chromatin remodeling, Young Adult, MOTIFS, DOMAIN, Intellectual Disability, Genes, Regulator, Genetics, medicine, Humans, Missense mutation, Amino Acid Sequence, HELICASE, Child, Coffin–Siris syndrome, Exome sequencing, Base Sequence, biology, Facies, Infant, Helicase, Sequence Analysis, DNA, Chromatin Assembly and Disassembly, medicine.disease, Molecular biology, CANCER, FAMILY, DELINEATION, Nicolaides–Baraitser syndrome, Child, Preschool, biology.protein, COMPLEXES, Sequence Alignment, Transcription Factors
Abstract

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.

Published
2012
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12. Female with hypohidrotic ectodermal dysplasia and de novo (X;9) translocation

Author

Kay D. MacDermot and Maj Hultén

Subjects
Genetics, Pathology, medicine.medical_specialty, X Chromosome, Genetic Linkage, Breakpoint, Chromosome 9, Chromosomal translocation, Biology, medicine.disease, Fibroblast cell line, Translocation, Genetic, Cell Line, Ectodermal Dysplasia, Genetic linkage, Cell culture, Intellectual Disability, medicine, Humans, Female, Hypohidrotic ectodermal dysplasia, Genetics (clinical), X chromosome
Abstract

We present here a historical documentation of a female with X-linked hypohidrotic ectodermal dysplasia (XHED) and a de novo X/9 chromosome translocation. The patient was verbally reported by Dr. P.L. J. Cook to the HGM conference in 1973, but was subsequently lost to follow up. We have since traced her and confirmed the diagnosis of XHED with moderately severe mental retardation. According to Dr. P. L. J. Cook's records, fibroblast cell line AnLy GMO 705, was derived from this patient. Another female with a de novo X/12 chromosome translocation and hypohidrotic ectodermal dysplasia was recently reported. In both cases, the X chromosome breakpoint appears to be at Xq13.1.

Published
1990
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13. Radial ray defect and Duane anomaly: Report of a family with autosomal dominant transmission

Author

Robin M. Winter, Kay D. MacDermot, and James F. Reynolds

Subjects
Adult, Eye Movements, Offspring, Anal Canal, Urogenital Abnormality, Anatomy, Middle Aged, Biology, Autosomal dominant transmission, Duane Retraction Syndrome, Pedigree, Absent thumb, Radius, Thumb, Anal stenosis, Clinical investigation, Humans, Abnormalities, Multiple, Female, Genetics (clinical), Genes, Dominant
Abstract

We report on a family in which a mother and her 2 offspring presented with bilateral radial defects and absent thumbs. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis. Clinical investigation showed no skeletal, cardiac, or urogenital abnormalities. Autosomal dominant transmission of radial defects is suggested, with Duane anomaly and anal stenosis representing manifestations of the same gene.

Published
1987
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14. The rate of purine synthesis de nova in blood mononuclear cells in vitro from patients with familial hyperuricaemic nephropathy

Author

Jennifer Allsop, Richard W. E. Watts, and Kay D. Macdermot

Subjects
Adult, Male, medicine.medical_specialty, Erythrocytes, Adolescent, Gout, Lesch-Nyhan Syndrome, Adenine phosphoribosyltransferase, Biology, Lymphocyte Activation, Peripheral blood mononuclear cell, Excretion, Internal medicine, medicine, Humans, Lymphocytes, Purine metabolism, Child, Nucleotide salvage, Aged, chemistry.chemical_classification, General Medicine, Syndrome, Middle Aged, Pedigree, Uric Acid, Endocrinology, Enzyme, chemistry, Hypoxanthine-guanine phosphoribosyltransferase, Purines, Child, Preschool, Immunology, Female, Kidney Diseases, Hypoxanthine Phosphoribosyltransferase
Abstract

1. We have measured the rate of purine synthesis de novo in blood mononuclear cells in vitro and the activities of the purine salvage enzymes [hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8), adenine phosphoribosyltransferase (APRT; EC 2.4.2.7)] and ribosephosphate pyrophosphokinase (PP-ribose-P synthetase;EC 2.7.6.1)] and the concentration of phosphoribosylpyrophosphate (PP-ribose-P) in the erythrocytes of affected family members. 2. These subjects belong to families where hyperuricaemia and renal failure occur together early in life, and the genetic transmission follows an autosomal dominant mode of inheritance. We term this syndrome, familial hyperuricaemic nephropathy. 3. No significant differences were detected in either the rates of purine synthesis de novo in vitro between the index patients and the control subjects with respect to the enzyme activities or the PP-ribose-P concentrations. Two groups of controls were used, healthy individuals and patients with a comparable degree of renal failure due to non-immune complex renal disease. 4. Mononuclear cells from patients with Lesch-Nyhan syndrome (congenital HPRT deficiency) showed the expected acceleration of purine synthesis de novo in vitro. 5. The accelerated purine synthesis de novo in vitro associated with phytohaemagglutinin-induced lymphocyte transformation was detectable by the method used. 6. We conclude that familial hyperuricaemic nephropathy is not due to a metabolic lesion which causes accelerated purine synthesis de novo. This suggests that the primary abnormality may be a failure of the renal tubular net excretion of urate.

Published
1984

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