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1. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Author: Charlotte Gehin, Museer A. Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M. Adeyemi, Erica H. Gerkes, Alexander P.A. Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R. Jones, Stefano Zamuner, Luciano A. Abriata, Vidya Kunnathully, Brandon E. Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W. van Bon, Rolph Pfundt, Marjolein H. Willemsen, Jolanda H. Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R. Fagerberg, Christoph P. Beier, Martin J. Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S. Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis B.R. Maddocks, Jennifer M. Bain, Musadiq A. Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L. Champaigne, Michael J. Friez, Ellen B. Richardson, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Yask Gupta, Tze Y. Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E. Burke, Ana Marjia Jakšić, Brian D. McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D’Angelo, and Vincenzo A. Gennarino
Subjects: Cell biology, Genetics, Medicine
Abstract: Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
Published: 2023
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2. Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia.

Author: Hildegard Nikki Hall, Hemant Bengani, Robert B Hufnagel, Giuseppe Damante, Morad Ansari, Joseph A Marsh, Graeme R Grimes, Alex von Kriegsheim, David Moore, Lisa McKie, Jamalia Rahmat, Catia Mio, Moira Blyth, Wee Teik Keng, Lily Islam, Meriel McEntargart, Marcel M Mannens, Veronica Van Heyningen, Joe Rainger, Brian P Brooks, and David R FitzPatrick
Subjects: Medicine, Science
Abstract: Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or microphthalmia (with no detectable PAX6 mutation) with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. These mutations occurred de novo in 3/5 families, with the remaining families being compatible with autosomal dominant inheritance. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes. Substitutions of the same codon (Arg51) in MAB21L2, a close homolog of MAB21L1, cause severe ocular and skeletal malformations in humans and mice. The predicted nucleotidyltransferase function of MAB21L1 could not be demonstrated using purified protein with a variety of nucleotide substrates and oligonucleotide activators. Induced expression of GFP-tagged wildtype and mutant MAB21L1 in human cells caused only modest transcriptional changes. Mass spectrometry of immunoprecipitated protein revealed that both mutant and wildtype MAB21L1 associate with transcription factors that are known regulators of PAX6 (MEIS1, MEIS2 and PBX1) and with poly(A) RNA binding proteins. Arg51 substitutions reduce the association of wild-type MAB21L1 with TBL1XR1, a component of the NCoR complex. We found limited evidence for mutation-specific interactions with MSI2/Musashi-2, an RNA-binding proteins with effects on many different developmental pathways. Given that biallelic loss-of-function variants in MAB21L1 result in a milder eye phenotype we suggest that Arg51-altering monoallelic variants most plausibly perturb eye development via a gain-of-function mechanism.
Published: 2022
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3. Variable neurodevelopmental and morphological phenotypes of carriers with 12q12 duplications

Author: Lynnea Myers, Moira Blyth, Kamran Moradkhani, Dubravka Hranilović, Sam Polesie, Johan Isaksson, Ann Nordgren, Maja Bucan, Marie Vincent, Sven Bölte, Britt‐Marie Anderlid, and Kristiina Tammimies
Subjects: ADHD, autism spectrum disorder, chromosome 12, duplication, phenotype, Genetics, QH426-470
Abstract: Abstract Background Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature. Methods We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb. Results The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication. Conclusion This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs.
Published: 2020
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4. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants [version 1; referees: 2 approved]

Author: Katrina Tatton-Brown, Anna Zachariou, Chey Loveday, Anthony Renwick, Shazia Mahamdallie, Lise Aksglaede, Diana Baralle, Daniela Barge-Schaapveld, Moira Blyth, Mieke Bouma, Jeroen Breckpot, Beau Crabb, Tabib Dabir, Valerie Cormier-Daire, Christine Fauth, Richard Fisher, Blanca Gener, David Goudie, Tessa Homfray, Matthew Hunter, Agnete Jorgensen, Sarina G. Kant, Cathy Kirally-Borri, David Koolen, Ajith Kumar, Anatalia Labilloy, Melissa Lees, Carlo Marcelis, Catherine Mercer, Cyril Mignot, Kathryn Miller, Katherine Neas, Ruth Newbury-Ecob, Daniela T. Pilz, Renata Posmyk, Carlos Prada, Keri Ramsey, Linda M. Randolph, Angelo Selicorni, Deborah Shears, Mohnish Suri, I. Karen Temple, Peter Turnpenny, Lionel Val Maldergem, Vinod Varghese, Hermine E. Veenstra-Knol, Naomi Yachelevich, Laura Yates, Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Research Study, Deciphering Developmental Disorders (DDD) Study, and Nazneen Rahman
Subjects: Medicine, Science
Abstract: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS
Published: 2018
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5. A Report of Novel STIM1 Deficiency and 6-Year Follow-Up of Two Previous Cases Associated with Mild Immunological Phenotype

Author: Laura Rice, Yasser M. El-Sherbiny, Karen Pysden, Sinisa Savic, Moira Blyth, Rashida Anwar, Claire Stockdale, Clive Carter, Ian R. Berry, Yousang Gwack, Sean O’Riordan, Sonal Srikanth, and Roger Rushambuza
Subjects: medicine.medical_specialty, Medical microbiology, business.industry, STIM1 DEFICIENCY, Immunology, Immunology and Allergy, Medicine, Immunological phenotype, business
Published: 2019

6. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), 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), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], 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 Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, 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), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and 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 )
Subjects: CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019

7. Cerebral hypomyelination associated with biallelic variants of FIG4

Author: Chloe A Stutterd, Miriam Fanjul-Fernández, Moira Blyth, Tiong Yang Tan, Victoria Rodriguez-Casero, Simon Sadedin, Paul J. Lockhart, Ian Craven, Daniel Warren, John H. Livingston, Adeline Vanderver, John Christodoulou, Gayatri Vadlamani, Ian R. Berry, Jonathan B Ruddle, Guy M. Lenk, Susan M. White, Susan Gibb, Lydia Green, Richard J. Leventer, Olga Skibina, Miriam H. Meisler, and Cas Simons
Subjects: Genetics, 0303 health sciences, 030305 genetics & heredity, Leukodystrophy, Biology, medicine.disease, Compound heterozygosity, Endolysosome, Oligodendrocyte, Leukoencephalopathy, 03 medical and health sciences, Exon, Peripheral neuropathy, medicine.anatomical_structure, medicine, Cerebral hypomyelination, Genetics (clinical), 030304 developmental biology
Abstract: The lipid phosphatase gene FIG4 is responsible for Yunis-Varon syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
Published: 2019

8. Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

Author: David A. Parry, Carol-Anne Martin, Philip Greene, Joseph A. Marsh, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, A. Giess, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, A. Orioli, C. Patch, D. Perez-Gil, M.B. Pereira, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, S.C. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, M. Tanguy, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Moira Blyth, Helen Cox, Deirdre Donnelly, Lynn Greenhalgh, Stephanie Greville-Heygate, Victoria Harrison, Katherine Lachlan, Caoimhe McKenna, Alan J. Quigley, Gillian Rea, Lisa Robertson, Mohnish Suri, and Andrew P. Jackson
Subjects: 0301 basic medicine, Microcephaly, Laminopathy, laminopathy, Biology, Brief Communication, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Exome, Genetics (clinical), Genetics, Progeria, Lamin Type B, primary microcephaly, Laminopathies, medicine.disease, Phenotype, neurodevelopmental disorder, 030104 developmental biology, LMNB1, LMNB2, Nuclear lamina, 030217 neurology & neurosurgery, Lamin
Abstract: PurposeLamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined.MethodsWe investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes.ResultsStarting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments.ConclusionWe identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.
Published: 2021
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9. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author: Enrico D.H. Konrad, Niels Nardini, Almuth Caliebe, Inga Nagel, Dana Young, Gabriella Horvath, Stephanie L. Santoro, Christine Shuss, Alban Ziegler, Dominique Bonneau, Marlies Kempers, Rolph Pfundt, Eric Legius, Arjan Bouman, Kyra E. Stuurman, Katrin Õunap, Sander Pajusalu, Monica H. Wojcik, Georgia Vasileiou, Gwenaël Le Guyader, Hege M. Schnelle, Siren Berland, Evelien Zonneveld-Huijssoon, Simone Kersten, Aditi Gupta, Patrick R. Blackburn, Marissa S. Ellingson, Matthew J. Ferber, Radhika Dhamija, Eric W. Klee, Meriel McEntagart, Klaske D. Lichtenbelt, Amy Kenney, Samantha A. Vergano, Rami Abou Jamra, Konrad Platzer, Mary Ella Pierpont, Divya Khattar, Robert J. Hopkin, Richard J. Martin, Marjolijn C.J. Jongmans, Vivian Y. Chang, Julian A. Martinez-Agosto, Outi Kuismin, Mitja I. Kurki, Olli Pietiläinen, Aarno Palotie, Timothy J. Maarup, Diana S. Johnson, Katja Venborg Pedersen, Lone W. Laulund, Sally A. Lynch, Moira Blyth, Katrina Prescott, Natalie Canham, Rita Ibitoye, Eva H. Brilstra, Marwan Shinawi, Emily Fassi, Heinrich Sticht, Anne Gregor, Hilde Van Esch, Christiane Zweier, Graduate School, Clinical Genetics, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Center for Population, Health and Society, Centre of Excellence in Complex Disease Genetics, and Aarno Palotie / Principal Investigator
Subjects: Male, CCCTC-Binding Factor, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Drosophila Proteins, Missense mutation, TOOL, Genetics(clinical), Child, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, biology, GENE ONTOLOGY, neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMANS, Chromatin, 3. Good health, DROSOPHILA, Drosophila melanogaster, intellectual disability, LIBRARY, Female, INACTIVATION, Life Sciences & Biomedicine, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], EXPRESSION, DATABASE, Mutation, Missense, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Animals, Gene, 030304 developmental biology, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Profiling, biology.organism_classification, medicine.disease, CTCF, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, 030217 neurology & neurosurgery, Transcription Factors, chromatin organization
Abstract: PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published
Published: 2019

10. Enhancing inclusion of diverse populations in genomics: A competence framework

Author: Roiyah Saltus, Mushtaq Ahmed, Juping Yu, Moira Blyth, Eamonn Sheridan, Saghira Malik Sharif, Maggie Kirk, and Emma Tonkin
Subjects: Medical education, education.field_of_study, Genome, Human, Population, Ethnic group, Genomics, Precision medicine, Geography, Rare Diseases, Cultural diversity, Ethnicity, Humans, Cultural Competency, Precision Medicine, education, Competence (human resources), Cultural competence, Exome, Genetics (clinical), Minority Groups
Abstract: Genomic knowledge and technology have developed rapidly over the last decade and increased our capabilities to diagnose and manage rare diseases. However, current genomic datasets lack ethnic diversity as many genomic studies have focused on participants of white European ancestry. Studies, such as the Deciphering Developmental Disorders study, have been available to participants of any ancestry but have been unsuccessful in recruiting diverse populations. The inclusion of diverse populations in exome and genome sequencing is important to ensure that clinical benefits of genomics advances are equally shared among all populations and to advance scientific knowledge. Our clinical and research experience with the British Pakistani population (the largest ethnic minority in Yorkshire and Humber, accounting for 4.3% of the population) has fostered the development of an innovative cultural competence framework to enhance the inclusion of diverse populations in clinical genomic research and service provision. The application of this framework has the potential to guide healthcare professionals to develop a wide range of competences, so they are ready to embrace genomic advances in order to improve health outcomes for all patients. This practice model will inform precision medicine and improve access of diverse populations to genomic studies. Although based upon work with the Pakistani population in the UK, it is anticipated that the model would be broadly applicable to all underrepresented populations across the world.
Published: 2019

11. Carbamazepine Improves Apneic Episodes in Congenital Central Hypoventilation Syndrome (CCHS) With a Novel PHOX2B Exon 1 Missense Mutation

Author: Schaida Schirwani, Karen Pysden, Philip Chetcuti, and Moira Blyth
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Nervous system, business.industry, Apnea, Carbamazepine, Congenital central hypoventilation syndrome, medicine.disease, Bioinformatics, Hypoventilation, 03 medical and health sciences, Exon, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Neurology, Anesthesia, medicine, Homeobox, Missense mutation, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Pathogenic variants in Paired-Like Homeobox 2B (PHOX2B) gene cause congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by absent or reduced venti...
Published: 2017

12. RAF1-associated Noonan syndrome presenting antenatally with an abnormality of skull shape, subdural haematoma and associated with novel cerebral malformations

Author: Mitchell W Dillon, Moira Blyth, Daniel Warren, and Verity L. Hartill
Subjects: Adult, Male, 0301 basic medicine, DNA Mutational Analysis, Subdural haematoma, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, Genetic Association Studies, Genetics (clinical), Cerebral Cortex, Comparative Genomic Hybridization, medicine.diagnostic_test, business.industry, Noonan Syndrome, Skull, Infant, Magnetic resonance imaging, General Medicine, Anatomy, medicine.disease, Magnetic Resonance Imaging, Pedigree, Proto-Oncogene Proteins c-raf, Radiography, Hematoma, Subdural, Phenotype, 030104 developmental biology, Tomography x ray computed, medicine.anatomical_structure, Cerebral malformations, Mutation, Pediatrics, Perinatology and Child Health, Noonan syndrome, Female, Abnormality, Tomography, X-Ray Computed, business, 030217 neurology & neurosurgery
Published: 2017

13. Rubinstein–Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum

Author: Shu Yau, Mohnish Suri, S. Lillis, Shelagh Joss, Muriel Holder-Espinasse, Emma Hobson, Jane A. Hurst, Emma Clement, William Reardon, Moira Blyth, Maryam Al-Shehhi, Sally Ann Lynch, Mark J. Hamilton, and Ruth Newbury-Ecob
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, Genotype, 030105 genetics & heredity, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual disability, medicine, Humans, Amino Acid Sequence, Syndactyly, Craniofacial, Child, Genetic Association Studies, Genetics (clinical), Exome sequencing, Rubinstein-Taybi Syndrome, Genetics, Rubinstein–Taybi syndrome, business.industry, Facies, Sequence Analysis, DNA, General Medicine, medicine.disease, CREB-Binding Protein, Phenotype, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Female, Anatomy, business, Haploinsufficiency, E1A-Associated p300 Protein
Abstract: Rubinstein-Taybi syndrome (RTS) is an autosomal dominant neurodevelopmental disorder characterized by growth deficiency, broad thumbs and great toes, intellectual disability and characteristic craniofacial appearance. Mutations in CREBBP account for around 55% of cases, with a further 8% attributed to the paralogous gene EP300. Comparatively few reports exist describing the phenotype of Rubinstein-Taybi because of EP300 mutations. Clinical and genetic data were obtained from nine patients from the UK and Ireland with pathogenic EP300 mutations, identified either by targeted testing or by exome sequencing. All patients had mild or moderate intellectual impairment. Behavioural or social difficulties were noted in eight patients, including three with autistic spectrum disorders. Typical dysmorphic features of Rubinstein-Taybi were only variably present. Additional observations include maternal pre-eclampsia (2/9), syndactyly (3/9), feeding or swallowing issues (3/9), delayed bone age (2/9) and scoliosis (2/9). Six patients had truncating mutations in EP300, with pathogenic missense mutations identified in the remaining three. The findings support previous observations that microcephaly, maternal pre-eclampsia, mild growth restriction and a mild to moderate intellectual disability are key pointers to the diagnosis of EP300-related RTS. Variability in the presence of typical facial features of Rubinstein-Taybi further highlights clinical heterogeneity, particularly among patients identified by exome sequencing. Features that overlap with Floating-Harbor syndrome, including craniofacial dysmorphism and delayed osseous maturation, were observed in three patients. Previous reports have only described mutations predicted to cause haploinsufficiency of EP300, whereas this cohort includes the first described pathogenic missense mutations in EP300.
Published: 2016

14. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], 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), Institut de Génétique et Développement de Rennes (IGDR), 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 ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], 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), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, 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 ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019

15. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

16. A report of novel STIM1 deficiency and 6 year follow up of two previous cases associated with mild immunological phenotype

Author: Laura Rice, Claire Stockdale, Ian Berry, Sean O’Riordan, Karen Pysden, Rashida Anwar, Roger Rushanbuza, Moira Blyth, Sonal Srikanth, Yousang Gwack, Clive Carter, and Sinisa Savic
Subjects: inorganic chemicals
Abstract: Loss of function or null mutations of Stromal interaction molecule 1 (STIM1) are known to cause early-onset combined immunodeficiency (CID) disease with recurrent and chronic infections, autoimmunity, haemolytic anaemia, ectodermal dysplasia, muscular weakness and myalgia. here we report of novel STIM1 deficiency and 6 year follow up of two previous cases associated with mild immunological phenotype
Published: 2018

17. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Author: Lelliott C, Wendy D Jones, Helen V. Firth, Sebastian S. Gerety, Daniel A. King, Ajith Kumar, Mary O'Regan, Diana Rajan, Nicola Foulds, Judith A. Goodship, Jenny Lord, Angela F. Brady, Dominic J. McMullan, James Whitworth, Cecilia W. Lo, Morad Ansari, Emma Hobson, David R. FitzPatrick, Nadia Akawi, Jeremy F. McRae, Alejandro Sifrim, Peter D. Turnpenny, Shelagh Joss, Deborah Osio, Tomas W Fitzgerald, Caroline F. Wright, Audrey Smith, Richard Francis, Melissa Lees, Elena Prigmore, Charu Deshpande, Jeffrey C. Barrett, Trevor Cole, Stephen Clayton, Meena Balasubramanian, Nikolai Klena, Moira Blyth, George C. Gabriel, Elisabeth Rosser, Ganesh J. Swaminathan, Matthew E. Hurles, and Virginia Piombo
Subjects: Male, Protein-Arginine N-Methyltransferases, Candidate gene, medicine.medical_specialty, Genotype, Ubiquitin-Protein Ligases, Developmental Disabilities, Population, Cell Cycle Proteins, Genes, Recessive, Biology, Compound heterozygosity, Article, symbols.namesake, Genotype-phenotype distinction, Matrix Metalloproteinases, Secreted, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, education, Genetic Association Studies, Family Health, education.field_of_study, Genetic heterogeneity, Genetic Variation, Sequence Analysis, DNA, United Kingdom, Pedigree, Phenotype, Mendelian inheritance, symbols, Medical genetics, Female, human activities
Abstract: Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.
Published: 2015

18. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Author: Anna Zachariou, Peter D Turnpenny, Linda M. Randolph, Carlos E. Prada, Angelo Selicorni, Nazneen Rahman, Christine Fauth, Ajith Kumar, Deborah J. Shears, Melissa Lees, Valérie Cormier-Daire, Shazia Mahamdallie, Mieke C. Bouma, Kathryn G. Miller, Katherine Neas, Vinod Varghese, Deciphering Developmental Disorders Study, Renata Posmyk, Chey Loveday, Lise Aksglaede, Ruth Newbury-Ecob, Keri Ramsey, Laura Yates, Daniela T. Pilz, David A. Koolen, I. Karen Temple, Beau Crabb, Cyril Mignot, Katrina Tatton-Brown, Daniela Q.C.M. Barge-Schaapveld, Blanca Gener, Cathy Kirally-Borri, Mohnish Suri, Agnete Jørgensen, David Goudie, Catherine Mercer, Carlo Marcelis, Anthony Renwick, Lionel Val Maldergem, Diana Baralle, Naomi Yachelevich, Matthew F. Hunter, Hermine E. Veenstra-Knol, Sarina G. Kant, Moira Blyth, Tessa Homfray, Jeroen Breckpot, Anatalia Labilloy, Tabib Dabir, and Richard Fisher
Subjects: 0301 basic medicine, Joint hypermobility, Pediatrics, medicine.medical_specialty, viruses, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, Clinical study, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Kyphoscoliosis, overgrowth, Tatton-Brown-Rahman, business.industry, Articles, biochemical phenomena, metabolism, and nutrition, medicine.disease, Obesity, Hypotonia, 3. Good health, 030104 developmental biology, Current management, intellectual disability, 030220 oncology & carcinogenesis, DNMT3A, TATTON-BROWN-RAHMAN SYNDROME, medicine.symptom, business, Research Article
Abstract: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS. ispartof: Wellcome Open Res vol:3 pages:46- ispartof: location:England status: Published online
Published: 2018

19. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author: Katherine L. Helbig, Robert J. Lauerer, Jacqueline C. Bahr, Ivana A. Souza, Candace T. Myers, Betül Uysal, Niklas Schwarz, Maria A. Gandini, Sun Huang, Boris Keren, Cyril Mignot, Alexandra Afenjar, Thierry Billette de Villemeur, Delphine Héron, Caroline Nava, Stéphanie Valence, Julien Buratti, Christina R. Fagerberg, Kristina P. Soerensen, Maria Kibaek, Erik-Jan Kamsteeg, David A. Koolen, Boudewijn Gunning, H. Jurgen Schelhaas, Michael C. Kruer, Jordana Fox, Somayeh Bakhtiari, Randa Jarrar, Sergio Padilla-Lopez, Kristin Lindstrom, Sheng Chih Jin, Xue Zeng, Kaya Bilguvar, Antigone Papavasileiou, Qinghe Xing, Changlian Zhu, Katja Boysen, Filippo Vairo, Brendan C. Lanpher, Eric W. Klee, Jan-Mendelt Tillema, Eric T. Payne, Margot A. Cousin, Teresa M. Kruisselbrink, Myra J. Wick, Joshua Baker, Eric Haan, Nicholas Smith, Azita Sadeghpour, Erica E. Davis, Nicholas Katsanis, Mark A. Corbett, Alastair H. MacLennan, Jozef Gecz, Saskia Biskup, Eva Goldmann, Lance H. Rodan, Elizabeth Kichula, Eric Segal, Kelly E. Jackson, Alexander Asamoah, David Dimmock, Julie McCarrier, Lorenzo D. Botto, Francis Filloux, Tatiana Tvrdik, Gregory D. Cascino, Sherry Klingerman, Catherine Neumann, Raymond Wang, Jessie C. Jacobsen, Melinda A. Nolan, Russell G. Snell, Klaus Lehnert, Lynette G. Sadleir, Britt-Marie Anderlid, Malin Kvarnung, Renzo Guerrini, Michael J. Friez, Michael J. Lyons, Jennifer Leonhard, Gabriel Kringlen, Kari Casas, Christelle M. El Achkar, Lacey A. Smith, Alexander Rotenberg, Annapurna Poduri, Alba Sanchis-Juan, Keren J. Carss, Julia Rankin, Adam Zeman, F. Lucy Raymond, Moira Blyth, Bronwyn Kerr, Karla Ruiz, Jill Urquhart, Imelda Hughes, Siddharth Banka, Ulrike B.S. Hedrich, Ingrid E. Scheffer, Ingo Helbig, Gerald W. Zamponi, Holger Lerche, Heather C. Mefford, Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Edward Smith, and John Wiener
Subjects: Male, 0301 basic medicine, Movement disorders, Task Force for Neonatal Genomics, Contracture/genetics, Neurodegenerative, Bioinformatics, Neurodevelopmental Disorders/genetics, Infantile, Medical and Health Sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Epilepsy/genetics, Spasms, Epilepsy, Spasms, Infantile/genetics, 0302 clinical medicine, R-Type, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Cation Transport Proteins, Genetics (clinical), Pediatric, Genetics & Heredity, Arthrogryposis, 0303 health sciences, Voltage-dependent calcium channel, Epileptic encephalopathy, Deciphering Developmental Disorders Study, Biological Sciences, Hypotonia, 3. Good health, CACNA1E, Genetic Variation/genetics, Child, Preschool, Neurological, Female, Megalencephaly/genetics, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Contracture, Adolescent, Dyskinesias/genetics, Biology, Article, arthrogryposis, 03 medical and health sciences, Genetics, medicine, Humans, Preschool, Calcium Channels, R-Type/genetics, 030304 developmental biology, Muscle contracture, Dyskinesias, business.industry, Calcium channel, Cation Transport Proteins/genetics, Neurosciences, Macrocephaly, Genetic Variation, Correction, Infant, medicine.disease, Human genetics, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, ion channel, calcium channel, Calcium Channels, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Published: 2018

20. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017

21. Pallister-Killian syndrome: a study of 22 British patients

Author: Viv K. Maloney, John A. Crolla, Diana Baralle, Morag N. Collinson, Sarah J. Beal, I. Karen Temple, Moira Blyth, and Shuwen Huang
Subjects: Pediatrics, medicine.medical_specialty, Population, Chromosome Disorders, Physical examination, Pallister–Killian syndrome, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, education, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, education.field_of_study, Chromosomes, Human, Pair 12, medicine.diagnostic_test, Mosaicism, business.industry, medicine.disease, United Kingdom, Phenotype, Tetrasomy, Cohort, Medical genetics, business, Fluorescence in situ hybridization
Abstract: Background Pallister-Killian syndrome is a rare, sporadic condition caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). The main features are intellectual disability, seizures, dysmorphic features and a variety of congenital malformations. Most available information comes from individual case reports. We report the results of a British study into Pallister-Killian syndrome, which is the first to provide comprehensive data on a population-based sample. Method A detailed phenotypical study was carried out in Great Britain. All individuals with Pallister-Killian syndrome were eligible to participate. Each participant underwent a structured history, developmental assessment and clinical examination. Buccal mucosal samples were analysed by interphase fluorescence in situ hybridization (FISH) and blood samples by array comparative genomic hybridization (CGH). Genotype-phenotype correlations were sought in these tissues and existing skin biopsy reports. Results Twenty-two patients with Pallister-Killian syndrome, ranging from 4 months to 31 years were recruited and comprehensive data on each obtained. The birth incidence was 5.1 per million live births. Array CGH only suggested the diagnosis in 15.8% but buccal FISH could have made the diagnosis in 75.0%. There was no genotype-phenotype correlation in any of the tissues studied. This study shows that the high birth weights and profound intellectual disability classically described in Pallister-Killian syndrome are not universal. Mild or moderate intellectual disability was present in 27.6% of this cohort and all birth weights were within 2.67SD of the mean. New features which have not previously been recognised as part of Pallister-Killian syndrome include anhydrosis/ hypohydrosis and episodic hyperventilation, suggesting involvement of the autonomic system.
Published: 2015

22. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author: Patrick Cossette, Zoha Kibar, Maxime Cadieux-Dion, Helen Brittain, Andrew E. Fry, Emily Fassi, Edward Blair, Simone Martinelli, Paul J. Benke, Guy D'Anjou, Alexandre D. Laporte, Berge A. Minassian, Sylvia Stockler, Tyson L Ware, David R. FitzPatrick, Weimin Bi, Amy L Schneider, Jill A. Rosenfeld, Shekeeb S. Mohammad, Jacques L. Michaud, Carlos A. Bacino, Joss Shelagh, Samuel F. Berkovic, Stéphane Auvin, Yunru Shao, Sylvia Dobrzeniecka, Kelly Mo, Cory Tam, Nicole Corsten-Janssen, Wendy K. Chung, Renee-Myriam Boucher, Alain Verloes, Fadi F. Hamdan, Bronwyn Kerr, Frédéric Tran Mau-Them, Martina Bebin, Philippe M. Campeau, Dara V.F. Albert, Guy A. Rouleau, Quinn Stein, Anne Lortie, Susan M. Hiatt, Lubov Blumkin, Boris Keren, Dan Spiegelman, Saadet Mercimek-Mahmutoglu, Ronald G. Lafrenière, Marie-Christine Nougues, Rhys H. Thomas, Erica H. Gerkes, Elsa Rossignol, Bruno Dallapiccola, Klaas J. Wierenga, Natalie Canham, Monica H. Wojcik, Caroline Meloche, Moira Blyth, Cyril Mignot, Heather C Mefford, Ledia Brunga, D. L. Jones, François Dubeau, Kyle Retterer, James J. O'Byrne, Christine Massicotte, Vincenzo Leuzzi, Caroline Nava, Ingrid E. Scheffer, Erik-Jan Kamsteeg, Cyrus Boelman, Megan T. Cho, Gabriela Purcarin, Brigid M. Regan, Jean Monlong, Simon Girard, Philippe Major, Marguerite Miguet, Katrin Õunap, Yu Chi Liu, Guillaume Bourque, Myriam Srour, Ousmane Diallo, Emilie Riou, Lionel Carmant, Seema R. Lalani, Christina Nassif, Robert Roger Lebel, Anna Lehman, Georgie Hollingsworth, Stéphanie Jacques, Sunita Venkateswaran, Marco Tartaglia, Candace T. Myers, Ange-Line Bruel, Danielle M. Andrade, Imad Jarjour, Peyman Bizargity, Sara J. Dorison, Jane A. Hurst, Richard E. Frye, Lynette G. Sadleir, Alan Donaldson, Fernando Scaglia, Philippe Lemay, Paola Diadori, Laura Davis-Keppen, Division of Genetic Medicine [Seattle], University of Washington [Seattle], Centre hospitalier universtaire de Montréal, Université de Montréal, Baylor College of Medicine ( BCM ), Baylor College of Medicine, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Clinical Genetics Department, St Michael's Hospital, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, Regional Genetic Service, St Mary's Hospital, Manchester, SUNY Upstate Medical University, 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 ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Robert Debré, Universitätsklinikum Leipzig, Institute of Plant and Microbial Biology, Academia Sinica, Istituto di Genetica Medica, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita', Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], 'Personal Protection Against Vectors' working group ( PPAV ), PPAV working group, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], McGill University and Genome Quebec Innovation Centre, Center of Excellence in Neuromics, University of Montreal, The Hospital for sick children [Toronto] ( SickKids ), CHU Sainte Justine [Montréal], Genome Canada Genome Quebec Jeanne and Jean-Louis Levesque Foundation Michael Bahen Chair in Epilepsy Research Ontario Brain Institute McLaughlin Foundation University of Toronto National Institute of Neurological Disorders and Stroke RO1 NS069605 University of Toronto McLaughlin Accelerator Grant in Genomic Medicine MC-2013-08, Baylor College of Medicine (BCM), Baylor University, State University of New York (SUNY), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Personal Protection Against Vectors' working group (PPAV), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), The Hospital for sick children [Toronto] (SickKids), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and 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 et Marie Curie - Paris 6 (UPMC)
Subjects: Male, 0301 basic medicine, Candidate gene, medicine.medical_specialty, medical genetics, glycosylation, Nonsense mutation, Genome-wide association study, Gene mutation, Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, severe intellectual disability, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, children, Recurrence, Seizures, Genetic linkage, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Journal Article, Genetics, medicine, Humans, Child, disorders, Genetics (clinical), Genetic association, Brain Diseases, disease, cis-prenyltransferase, Genome, Human, structural basis, medicine.disease, diphosphate synthase, 030104 developmental biology, Child, Preschool, Mutation, Medical genetics, Female, nogo-b receptor, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study, Meta-Analysis
Abstract: Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
Published: 2017

23. Homozygosity for a novel deletion downstream of theSHOXgene provides evidence for an additional long range regulatory region with a mild phenotypic effect

Author: Vivienne Maloney, Moira Blyth, David J. Bunyan, and Emma-Jane Taylor
Subjects: Adult, Consanguineous family, Regulatory Sequences, Nucleic Acid, Biology, Osteochondrodysplasias, Gene Deletions, Regulatory region, Consanguinity, Shox gene, Short Stature Homeobox Protein, Genetics, medicine, Humans, Coding region, Genetic Association Studies, Growth Disorders, In Situ Hybridization, Fluorescence, Genetics (clinical), Aged, Sequence Deletion, Homeodomain Proteins, Comparative Genomic Hybridization, Langer mesomelic dysplasia, Point mutation, Homozygote, Middle Aged, medicine.disease, Phenotype, Molecular biology, Pedigree, Enhancer Elements, Genetic, Female
Abstract: Léri-Weill dyschondrosteosis is caused by heterozygous mutations in SHOX or its flanking sequences, including whole or partial gene deletions, point mutations within the coding sequence, and deletions of downstream regulatory elements. The same mutations when biallelic cause the more severe Langer Mesomelic dysplasia. Here, we report on a consanguineous family with a novel deletion downstream of SHOX in which homozygously deleted individuals have a phenotype intermediate between Léri-Weill dyschondrosteosis and Langer Mesomelic dysplasia while heterozygously deleted individuals are mostly asymptomatic. The deleted region is distal to all previously described 3' deletions, suggesting the presence of an additional regulatory element, deletions of which have a milder, variable phenotypic effect.
Published: 2014

24. 21q21 deletion involving NCAM2: Report of 3 cases with neurodevelopmental disorders

Author: Florence Petit, Matthieu Decamp, Moira Blyth, Joris Andrieux, Ghislaine Plessis, Maria Pendlebury, and Jean-Marie Cuisset
Subjects: Male, Genetics, Chromosomes, Human, Pair 21, Developmental Disabilities, Neural Cell Adhesion Molecule L1, General Medicine, Biology, medicine.disease, Phenotype, Fasciculation, Child, Preschool, medicine, Humans, Autism, Female, Neural cell adhesion molecule, Chromosome Deletion, medicine.symptom, Child, Neural Cell Adhesion Molecules, Gene, Genetics (clinical), Genetic association, Comparative genomic hybridization
Abstract: Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.
Published: 2015

25. Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings

Author: Francois P. Bernier, Sarah F. Smithson, Danielle C. Lynch, C Wallis, Debbie Shears, Jenny Morton, Elaine H. Zackai, Melissa Lees, Amaka C. Offiah, Usha Kini, Angela Barnicoat, Nobue Itasaki, Emma Wakeling, Tom Hilliard, Jillian S. Parboosingh, Jill Clayton-Smith, Alistair Calder, Simon Langton-Hewer, Angus John Clarke, Rebecca Hewitson, Elizabeth J. Bhoj, Richard H Scott, Madeleine J. Tooley, Michael Saunders, Tessa Homfray, Moira Blyth, and Peter Davis
Subjects: 0301 basic medicine, Male, Microcephaly, Pathology, medicine.medical_specialty, Adolescent, Micrognathism, Ribs, Scoliosis, 030105 genetics & heredity, snRNP Core Proteins, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Craniofacial, Child, Genetics (clinical), Rib cage, Respiratory distress, business.industry, Hyoid bone, Horseshoe kidney, Infant, Exons, medicine.disease, Cleft Palate, 030104 developmental biology, Child, Preschool, Mutation, Pierre Robin syndrome, Spliceosomes, Female, business
Abstract: Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.
Published: 2015

26. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author: Sixto García-Miñaur, Ratna Veeramachaneni, Susan Price, Nicola Ragge, Kay Metcalfe, Graeme C.M. Black, Christopher P. Bennett, William Reardon, Alex Magee, Soo Mi Park, Jill Clayton-Smith, Nicole Revencu, Bruce Castle, Christine Oley, Wayne W.K. Lam, Vivienne McConnell, Deirdre E. Donnelly, Deepthi De Silva, Andrew E. Fry, I. Karen Temple, Judith A. Goodship, Helen Kingston, Gunnar Houge, Fiona Stewart, Sally J. Davies, Frances Elmslie, John Tolmie, Sancha Bunstone, Harinder Gill, Emma Howard, Shehla Mohammed, Moira Blyth, Michael Parker, Emma Hobson, Dian Donnai, Michael Wright, Kate Chandler, Amanda L. Collins, Susann Schweiger, Katherine Lachlan, Alex Henderson, Richard Gibbons, Siren Berland, Audrey Smith, Sally Ann Lynch, Pradeep Vasudevan, Bronwyn Kerr, Richard Fisher, Meriel McEntagart, Jenny Morton, Siddharth Banka, Yanick J. Crow, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: Biology, medicine.disease_cause, Article, Cohort Studies, Genetic Heterogeneity, Exon, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Epigenetics, Genetics (clinical), Mutation, Genetic heterogeneity, Cancer, Sequence Analysis, DNA, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Face, Female, Kabuki syndrome
Abstract: MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. © 2012 Macmillan Publishers Limited All rights reserved.
Published: 2011

27. Severe staphylococcal scalded skin syndrome in children

Author: Catalina M. Estela, Amber Young, and Moira Blyth
Subjects: Male, Pediatrics, medicine.medical_specialty, Critical Care, Burn Units, Water-Electrolyte Imbalance, Erythroderma, Critical Care and Intensive Care Medicine, Leukocyte Count, Enteral Nutrition, Intensive care, medicine, Humans, Child, Patient Care Team, Body surface area, LYELL SYNDROME, Leukopenia, business.industry, General Medicine, Length of Stay, Staphylococcal scalded skin syndrome, medicine.disease, Bandages, El Niño, Child, Preschool, Emergency Medicine, Fluid Therapy, Female, Surgery, Analgesia, Staphylococcal Scalded Skin Syndrome, medicine.symptom, Complication, business, Hyponatremia
Abstract: Staphylococcal scalded skin syndrome (SSSS) is a rare toxin-mediated condition caused by Staphylococcus aureus, which causes blistering and desquamation of the skin. Between November 2005 and April 2006, four children were admitted to critical care beds in the South West Regional Paediatric Burns Unit because of SSSS affecting more than 50% of the body surface area. Details of these cases are presented, highlighting the potential severity of the condition. The cases also illustrate that fluid overload is a common complication of the condition, despite hypovolaemia being the more obvious risk, and that both hyponatraemia and leukopenia are frequent findings. These summaries clearly demonstrate the need for paediatric critical care in a tertiary burns unit for children with SSSS affecting a large proportion of the body surface area. The cluster of admissions prompted us to write a management protocol for children with severe SSSS and a summary of this is provided. Most children with SSSS will initially present to general paediatric units, where mild cases will be managed, but severe cases should be promptly referred to a tertiary paediatric burns unit for multi-disciplinary care in a critical care environment.
Published: 2008

28. Phenotypic features of diploid/triploid mosaicism in an adult

Author: Paul Roberts, Alison Birch, Rosalyn Jewell, and Moira Blyth
Subjects: Genetics, Adult, Chromosome Aberrations, business.industry, Mosaicism, Diploid-Triploid Mosaicism, Developmental Disabilities, General Medicine, Phenotype, Pathology and Forensic Medicine, Polyploidy, Pediatrics, Perinatology and Child Health, Medicine, Humans, Female, Anatomy, business, Genetics (clinical)
Published: 2014

29. Amniotic bands in paternal half-siblings

Author: Moira Blyth and Katherine Lachlan
Subjects: Male, medicine.medical_specialty, Amniotic Band, Limb reduction, Familial amniotic bands, Pathology and Forensic Medicine, Constriction, Fathers, Pregnancy, medicine, Humans, Family history, Genetics (clinical), Fetus, Obstetrics, business.industry, Siblings, Infant, Newborn, Infant, Congenital malformations, General Medicine, Anatomy, Pedigree, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Amniotic Band Syndrome, business
Abstract: We present two paternal half-siblings with constriction rings and limb reduction deformities, which seem to have been caused by amniotic bands. Their father has no evidence of amniotic bands nor any other congenital malformations and there is no wider family history of such malformations. There are few other reports of familial amniotic bands and these are either in mother-child pairs, siblings or in distant relatives. This is the first report of recurrence in paternal half-siblings. Although no exact cause can be identified, this suggests that some genetic fetal factor, or factors, must be responsible for the amniotic bands in these cases.
Published: 2010

30. Expanding the tuberous sclerosis phenotype: mild disease caused by a TSC1 splicing mutation

Author: Diana Baralle, Moira Blyth, F. Lucy Raymond, Michela Raponi, Rebecca Treacy, and John R.W. Yates
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Mutation, Intron, Biology, medicine.disease_cause, medicine.disease, Tuberous sclerosis protein, Psychiatry and Mental health, Exon, Tuberous sclerosis, medicine.anatomical_structure, RNA splicing, medicine, Surgery, Neurology (clinical), TSC1, TSC2
Abstract: Tuberous sclerosis (TS) is an autosomal dominant disorder with variable expression, which causes epilepsy, mental retardation and hamartomas in many organ systems. TS is caused by mutations in two genes, TSC1 on 9q34 and TSC2 on 16p13.3. Mutations can be detected in approximately 85% of patients who meet the published consensus clinical diagnostic criteria.1–3 The remainder probably have mutations in intronic or promoter regions, which are not routinely screened, or are mosaic for the condition. Genotype–phenotype correlations have been slow to emerge in this disorder but TSC2 mutations tend to be associated with more severe disease than TSC1 mutations.2 3 Most TSC1 mutations are single base substitutions or small insertions/deletions, and cause protein truncation. A small number are putative splice site mutations but the effects on the proteins produced have not been studied in detail. Splicing is the process in which introns are excised from the RNA and exons joined together to form messenger RNA transcript, which is translated into the protein. We present a family with an unusually mild phenotype caused by a novel TSC1 splice site (SS) mutation. This proband was admitted to hospital following an episode of unconsciousness with cyanosis at 4.5 months of age. Cranial CT scan showed …
Published: 2010

31. Cover Image, Volume 170A, Number 5, May 2016

Author: Madeleine Tooley, Danielle Lynch, Francois Bernier, Jillian Parboosingh, Elizabeth Bhoj, Elaine Zackai, Alistair Calder, Nobue Itasaki, Emma Wakeling, Richard Scott, Melissa Lees, Jill Clayton-Smith, Moira Blyth, Jenny Morton, Debbie Shears, Usha Kini, Tessa Homfray, Angus Clarke, Angela Barnicoat, Colin Wallis, Rebecca Hewitson, Amaka Offiah, Michael Saunders, Simon Langton-Hewer, Tom Hilliard, Peter Davis, and Sarah Smithson
Subjects: Genetics, Genetics (clinical)
Published: 2016

32. A novel 2.43 Mb deletion of 7q11.22-q11.23

Author: Moira Blyth, John A. Crolla, Shuwen Huang, Sarah Beal, and Nicola Foulds
Subjects: Male, Williams Syndrome, LIMK1, Genetics, medicine, Humans, Gene, Base Pairing, Genetics (clinical), Sequence Deletion, Comparative Genomic Hybridization, biology, Chromosome, Infant, medicine.disease, Molecular biology, humanities, Peripheral pulmonary artery stenosis, Cosmid, biology.protein, Williams syndrome, Elastin, Supravalvular aortic stenosis, Chromosomes, Human, Pair 7, Gene Deletion
Abstract: We present a patient with a novel heterozygous deletion of 7q11.22-q11.23. Standard cytogenetic analysis using the ELN cosmid 82C and the ELN/ LIMK1 cosmid 34B FISH probes suggested a diagnosis of Williams syndrome. Although he has supravalvular aortic stenosis and peripheral pulmonary artery stenosis, which are common in this condition, he does not have the clinical gestalt of Williams syndrome. 44k oligo array CGH analysis showed a 2.43 Mb deletion, encompassing the proximal 1.43 kb of the Williams syndrome critical region and extending approximately 1 Mb beyond it. The deletion of further genes outside the Williams syndrome critical region does not appear to be having a phenotypic effect at present.
Published: 2008

33. A 2.3Mb deletion of 17q24.2-q24.3 associated with 'Carney Complex plus'

Author: I. Karen Temple, Viv K. Maloney, Moira Blyth, Shuwen Huang, and John A. Crolla
Subjects: Genetics, Microcephaly, Dysostosis, Infant, Nucleic Acid Hybridization, General Medicine, Laryngeal cleft, Biology, medicine.disease, Developmental disorder, medicine, Humans, Female, Syndactyly, medicine.symptom, Chromosome Deletion, Haploinsufficiency, Child, Carney complex, PRKAR1A, Genetics (clinical), In Situ Hybridization, Fluorescence, Chromosomes, Human, Pair 17
Abstract: We present a 12-year-old with a de novo interstitial deletion of approximately 2.3Mb in chromosome band 17q24.2-q24.3, which was identified by array CGH. The most characteristic features in this case are posterior laryngeal cleft and the presence of numerous freckles and lentigines in childhood. Growth restriction, microcephaly and moderate mental retardation are also prominent features but are frequently seen with other chromosomal anomalies. The microdeletion causes haploinsufficiency of PRKAR1A (protein kinase, cAMP-dependent, regulatory 1alpha), which is known to cause Carney Complex but this diagnosis alone does not account for all of her problems and she therefore has 'Carney Complex plus'. This report illustrates the practical benefits associated with a clear cytogenetic diagnosis, as regular endocrinological and cardiac screening is required.
Published: 2008

34. Severe Marfan syndrome due to FBN1 exon deletions

Author: Nicola Foulds, Claire L. S. Turner, David J. Bunyan, and Moira Blyth
Subjects: musculoskeletal diseases, Marfan syndrome, Proband, congenital, hereditary, and neonatal diseases and abnormalities, Systemic disease, Fibrillin-1, Biology, Fibrillins, Severity of Illness Index, Marfan Syndrome, Exon, Severity of illness, Genetics, medicine, Humans, Genetics (clinical), Point mutation, Microfilament Proteins, Infant, Exons, medicine.disease, Connective tissue disease, Radiography, Child, Preschool, Female, Fibrillin, Gene Deletion
Abstract: Marfan syndrome is an autosomal dominant condition, with manifestations mainly in the skeletal, ocular, and cardiovascular systems. The disorder is caused by mutations in fibrillin-1 gene (FBN1). The majority of these are family-specific point mutations, with a small number being predicted to cause exon-skipping. To date, there have only been five reports of in-frame exon deletions in FBN1, with the largest of these spanning three exons. Mosaicism is rarely recorded and has only been reported in the unaffected, or mildly affected, parents of probands. Here, we report on the clinical histories of two children with exon deletions in FBN1. Both have severe Marfan syndrome with significant signs in infancy. One patient has a deletion of exon 33, which has not previously been reported. The other has the largest reported deletion, which spans 37 exons, and also represents the first reported case of mosaicism in a patient with Marfan syndrome.
Published: 2008

35. Anophthalmia in fronto–facial–nasal dysplasia

Author: Diana Baralle and Moira Blyth
Subjects: Joint Instability, Male, medicine.medical_specialty, Adolescent, Foot Deformities, Congenital, Cleft Lip, Hearing Loss, Conductive, Hernia, Inguinal, Pathology and Forensic Medicine, Craniofacial Abnormalities, Text mining, Ectodermal Dysplasia, Intellectual Disability, Humans, Medicine, Abnormalities, Multiple, Autistic Disorder, Genetics (clinical), Scalp, Anophthalmia, Tooth Abnormalities, business.industry, Anophthalmos, General Medicine, medicine.disease, Dermatology, Cleft Palate, Facial Asymmetry, Scoliosis, Dysplasia, Pediatrics, Perinatology and Child Health, Anatomy, business
Published: 2011

36. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author: Nicola S. Cooper, S Samant, H Purnell, Claire L. S. Turner, A Vandersteen, Alex Magee, Susan Tomkins, Louise C. Wilson, L Greenhalgh, IK Temple, Irina Colgiu, A Duncan, G Cross, Susan E. Holder, C Wragg, Deirdre E. Donnelly, Nadia Akawi, Linda Sneddon, Eamonn Sheridan, Wendy D Jones, I Ellis, David Bourn, Joanna Poulton, Ingrid Simonic, R Singzon, Lisa Bradley, Matthew E. Hurles, Meena Balasubramanian, Dominic J. McMullan, Trevor Cole, Gillian Roberts, J Thomson, Moira Blyth, G Hollingsworth, Neeti Ghali, Alex Henderson, Zara Skitt, E Roberts, G Woods, David Goudie, J Awada, Caroline Langman, U Anjum, Martin O. Pollard, Usha Kini, Stephen Clayton, J Burn, Daniel M Barrett, Vka Kumar, Angela E. Douglas, Natalie Canham, Ruth Armstrong, Denise Williams, C Shaw-Smith, Lorraine Gaunt, S Ingram, Edward Blair, K Brunstrom, O. W.J. Quarrell, Ben Hutton, Nora Shannon, S Wallwark, Laura E Mason, Sarah F. Smithson, Jeremy F. McRae, Amanda L. Collins, Shane McKee, Katrina Prescott, Lara Cresswell, Sofia Douzgou, L Islam, C Deshpande, J Waters, Anna Middleton, S-M Park, Tarjinder Singh, Liu He, M Tein, T Fendick, B Kaemba, Tara Montgomery, Michael Wright, Jenny Morton, J Roberts, Emma Hobson, Caroline Mackie Ogilvie, Katrina Tatton-Brown, Lucy Jenkins, A Coates, Abhijit Dixit, Deborah J. Shears, Kath Smith, D. Baty, D Lim, D Cilliers, Richard Gibbons, Ruth Newbury-Ecob, M Squires, Nicola K. Ragge, Anneke Seller, E Kivuva, Kay Metcalfe, Fiona Stewart, K Marks, Elisabeth Rosser, R Fisher, Andrew E. Fry, Joan Paterson, Diana Wellesley, Dian Donnai, Christopher P. Bennett, Jonathan Berg, Ganesh J. Swaminathan, Lucy Raymond, Sally Ann Lynch, Pradeep C. Vasudevan, Rosemarie Davidson, Melita Irving, John Dean, Margo Whiteford, Melissa Lees, S Payne, K-R Ong, Emma Gray, M Holder, Dragana Josifova, Claire Kirk, McConnell, Helen Cox, Sarju G. Mehta, Elena Prigmore, Emma Shearing, Anand Saggar, Angela Barnicoat, Alejandro Sifrim, Nicola Foulds, Katherine Martin, Joanna Kaplanis, Sahar Mansour, Kirsty Ambridge, Clowes, A Procter, Z Miedzybrodzka, Katherine Lachlan, S Schweiger, E Maher, Allyson Ross, Simon Brent, C Sequeira, Tabib Dabir, Netravathi Krishnappa, Andrew Smith, B Bernhard, Andrew Green, Sara Widaa, Daniel A. King, Astrid Weber, Harinder Gill, Frances Flinter, Ruth McGowan, Siddharth Banka, Susan E. McNerlan, Elizabeth M. Sweeney, L Nevitt, Michael Parker, Hood Mugalaasi, AP Bevan, L Harrison, Varghese, Lucy Hildyard, Murday, G Kirby, S Clasper, Sutton, Clare Taylor, Andrew Jackson, A Selby, E Wilkinson, Miranda Splitt, Stuart Aitken, Shelagh Joss, Fiona Connell, Julie Vogt, Jill Clayton-Smith, Alan Fryer, N Pratt, Parthiban Vijayarangakannan, Shehla Mohammed, Susan Price, Wayne Lam, Peter D. Turnpenny, C Tysoe, Raheleh Rahbari, Marc Tischkowitz, N Williams, Tessa Homfray, Maria Bitner-Glindzicz, Helen Murphy, Meriel M. McEntagart, Sian Ellard, M Ahmed, R O'Shea, Andrew R. Norman, Daniel Perrett, Harrison, Philip Greene, David Moore, R Hawkins, DT Pilz, FitzPatrick, P Batstone, Esther Kinning, Caroline F. Wright, Yanick J. Crow, Kate Chandler, C Donnelly, Leema Robert, Straub, Susan M. Gribble, Philip Jones, D de Vries, K Evans, Simon J. Davies, Diana Baralle, E Miles, Jeffrey C. Barrett, A Lampe, Joshua C. Randall, Bruce Castle, K McKay, D Rice, Becky Treacy, Richard H Scott, Rosemary Kelsell, Angela F. Brady, Julian R. Sampson, J Jarvis, Laura Yates, R Sandford, Hayley Archer, M Yau, Mohnish Suri, Caroline Pottinger, Dhavendra Kumar, R. Taylor, Alison Kraus, L Bourdon, Alan Donaldson, S Everest, S Kazembe, Sian Morgan, C Longman, Ingrid Scurr, Alison Male, Ajoy Sarkar, Helen Kingston, Emma McCann, Julie M. Phipps, Andrea H. Németh, A Pridham, D Bohanna, C Gardiner, Diana Johnson, Tomas W Fitzgerald, Eleni A. Chatzimichali, A Dobbie, Diana Rajan, Frances Elmslie, Mohsan Alvi, Pendaran Roberts, Bronwyn Kerr, M D'Alessandro, Elizabeth A. Jones, Simon Holden, U Maye, Helen V. Firth, J Rankin, H. Stewart, S Naik, Adrian Tivey, Chirag N. Patel, Tanya Bayzetinova, G Lowther, G Devlin, A Torokwa, DJ Bunyan, Judith A. Goodship, Sarah Hewitt, Emma Wakeling, Christoffer Nellåker, S Wilcox, Saba Sharif, MN Collinson, C Brewer, Jacqueline Eason, C McWilliam, Jane A. Hurst, Angus John Clarke, Mervyn Humphreys, and Stephen W. Hellens
Subjects: Genetics, 0303 health sciences, education.field_of_study, Genetic heterogeneity, Population, Biology, Phenotype, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, education, Indel, Gene, Exome, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.AbbreviationsPTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study

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