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1. Genetic and chemotherapeutic causes of germline hypermutation

Author

Christopher A. Odhams, Giuseppe Gallone, Jeremy F. McRae, Angela Barnicoat, Joanna Kaplanis, Petr Danecek, Matthew D. C. Neville, Jenny Carmichael, Tim H. H. Coorens, Patrick J. O’Brien, Matthew E. Hurles, Raheleh Rahbari, Elena Prigmore, Helen V. Firth, Benjamin Ide, Rashesh Sanghvi, Loukas Moutsianas, and Patrick J. Short

Subjects
Genetics, Mutation, Germline mutation, DNA repair, Genetic variation, medicine, Somatic hypermutation, Disease, Biology, medicine.disease_cause, Genome, Germline
Abstract

SummaryMutation in the germline is the source of all evolutionary genetic variation and a cause of genetic disease. Previous studies have shown parental age to be the primary determinant of the number of new germline mutations seen in an individual’s genome. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 hypermutated individuals with between two and seven times more de novo single nucleotide variants (dnSNVs) than expected. In most of these families (8/12) the excess mutations could be attributed to the father. We determined that two of these families had genetic drivers of germline hypermutation, with the fathers carrying damaging genetic variation in known DNA repair genes, causing distinctive mutational signatures. For five families, by analysing clinical records and mutational signatures, we determined that paternal exposure to chemotherapeutic agents prior to conception was a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare and relatively modest in degree and that most hypermutated individuals will not have a genetic disease.

Published
2021

2. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

Author

David A. Stevenson, Karen Stals, Andrea Hanson-Kahn, Sian Ellard, Michael Bruccoleri, Clare E. Beesley, Emma Wakeling, Xiang-Jiao Yang, Matthew Wakeling, Sarah H. Elsea, Philippe M. Campeau, Angela Barnicoat, Meriel McEntagart, Richard Caswell, Charles Shaw-Smith, and Mary K. Kukolich

Subjects
Genetics, gain-of-function, biology, Regulatory site, Histone deacetylase 4, QH426-470, Chromosome 2q37 Deletion Syndrome, HDAC4, Phenotype, Article, Chromatin, Histone, intellectual disability, 14-3-3 binding, biology.protein, Molecular Medicine, Missense mutation, Binding site, Genetics (clinical)
Abstract

Summary Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder., Loss-of-function variants in histone deacetylase 4 (HDAC4) have been reported to cause brachydactyly-mental retardation (BDMR) syndrome through haploinsufficiency. This report describes 7 individuals with a phenotype distinct from BDMR, all with missense variants in a conserved 14-3-3 site, which are hypothesized to result in a novel gain-of-function effect in HDAC4.

Published
2020

3. ZMYND11‐related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum

Author

Tuula Rinne, Karen Low, Vijaya Ramachandran, Johanna C. Herkert, Michael Parker, Meena Balasubramanian, Helen Cox, Andrew E. Fry, Erica H. Gerkes, Deborah A Sival, Meriel McEntagart, Isabelle Marey, Mary O'Driscoll, Bert Callewaert, Perrine Charles, Fleur Vansenne, Suzanne Drury, Angela Barnicoat, Boris Keren, Wen-Hann Tan, Thabo M. Yates, Morgan Drucker, and Movement Disorder (MD)

Subjects
Male, ZMYND11, Genotype, Depressed nasal bridge, behavioral symptoms, Cell Cycle Proteins, Haploinsufficiency, Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, TRANSCRIPTION, Child, Gene, Alleles, Genetic Association Studies, Genetics (clinical), seizures, 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DELETION, 030305 genetics & heredity, Brachydactyly, Facies, Syndrome, gene expression regulation, medicine.disease, zinc fingers, GENE, Phenotype, Hypotonia, Nonsense Mediated mRNA Decay, DNA-Binding Proteins, intellectual disability, Child, Preschool, Mutation, Anteverted nares, Female, medicine.symptom, Co-Repressor Proteins
Abstract

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioural abnormalities and seizures. Only 11 affected individuals have been reported to‐date, and the phenotype associated with pathogenic variants in this gene have not been fully defined.\ud \ud Here, we present 16 additional patients with predicted pathogenic heterozygous variants in ZMYND11, including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11‐related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioural abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia.\ud \ud Most identified variants are likely to result in premature truncation and/or nonsense mediated decay. Two ZMYND11 variants located in the final exon ‐ p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg) ‐ are predicted to disrupt the MYND‐type zinc finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss‐of‐function.

Published
2020

4. 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

5. Corrigendum: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Rosaline Caumes, Andrea Berger, John Stone, Roberta Battini, Charles Marques Lourenço, Gerardine Quaghebeur, Nicholas A. Fletcher, Elliott H. Sherr, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Marco Henneke, Kanaga R. Sinnathuray, Pierre Landrieu, James O'Sullivan, Calvin Soh, Himanshu Goel, Patrick Ferreira, Katrin Õunap, Cheryl Hemingway, Laurence C. Goosey, Graham D. Pavitt, Hilde Van Esch, Prab Prabhakar, Yoann Rose, Jill E. Urquhart, Yanick J. Crow, Gabriela M. Baerlocher, Simon G. Williams, Mathieu P Rodero, Ram L. Kumar, Emma M. Jenkinson, Gillian I. Rice, Sarju G. Mehta, Adeline Vanderver, Timothy J. Malpas, Christopher J. Kershaw, Imke Metz, Edward Blair, Paul R. Kasher, Imelda Hughes, Patrick Revy, David Cassiman, Duccio Maria Cordelli, Angela Barnicoat, Andrea Whitney, Janice E. Brunstrom-Hernandez, Axel Panzer, Kristin W. Barañano, Liesbeth De Waele, Geraldine Aubert, Raphael Schiffmann, H. Stewart, Monika Haubitz, Rosalind J. Jefferson, Alan Fryer, Anthony Oojageer, Carolina Uggenti, John H. Livingston, Sam Griffiths-Jones, Christine E. G. van Mol, Johannes A. Buckard, Raymond T. O'Keefe, Lieven Lagae, Emma Wakeling, Sakkubai Naidu, Alex J. Fay, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Department of Medical Genetics, and HMNC Brain Health

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Biology, medicine.disease, Article, 3. Good health, Leukoencephalopathy, 03 medical and health sciences, 0302 clinical medicine, Cerebral microangiopathy, Genetics, medicine, 610 Medicine & health, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2017

6. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Author

Brian T. Wilson, Vasiliki Nakou, Henry Houlden, Angela Barnicoat, Joost Nicolai, Miriam S. Reuter, Patrick Rump, F Lucy Raymond, Nicholas W. Wood, Serena Barral, Sanjay Bhate, Jonathan R. Chubb, Manju A. Kurian, Michèl A.A.P. Willemsen, Esther Meyer, André Reis, Nicola Foulds, Shekeeb S Mohammed, Kathryn J. Peall, Patricia Limousin, Apostolos Papandreou, Margaret Kaminska, Magnus Nilsson, Russell C. Dale, Susan M. White, Paul Gissen, Hilla Ben-Pazi, Gregory Peters, Christopher Wragg, Zvi Israel, Jean-Pierre Lin, Sarah Wiethoff, Simon Pope, Deciphering Developmental Disorders Study, William A. Gahl, Alan Pittman, Niccolo E. Mencacci, Wui K. Chong, Margje Sinnema, Dagmar Wieczorek, Erik-Jan Kamsteeg, Martin Smith, A. Hills, John M.E. Nichols, Shane McKee, Keren J. Carss, Maya Topf, S Heales, Gidon Winter, Amber Boys, Hardev Pall, Peter D. Turnpenny, Camilo Toro, Julia Rankin, Jane A. Hurst, Reeval Segel, Nicholas Gutowski, Hagai Bergman, Niklas Darin, Shibalik Misra, Lucinda Carr, Agnel Praveen Joseph, Joanne Ng, Deborah Morrogh, David Arkadir, Detelina Grozeva, Adeline Ngoh, Daniel E. Lumsden, Belén Pérez-Dueñas, Prab Prabhakar, Kailash P. Bhatia, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, Male, Methyltransferase, Deep brain stimulation, Adolescent, Histone lysine methylation, DISORDERS, medicine.medical_treatment, VARIANTS, Bioinformatics, bcs, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], MECHANISMS, Histones, 03 medical and health sciences, BRAIN IRON ACCUMULATION, Genetics, medicine, KABUKI SYNDROME, Humans, Laryngeal dystonia, Dystonia, Regulation of gene expression, biology, Lysine, METHYLATION, NEURODEGENERATION, Nuclear Proteins, Histone-Lysine N-Methyltransferase, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], DNA-Binding Proteins, 030104 developmental biology, Histone, Histone methyltransferase, Mathematik, Mutation, biology.protein, Histone Methyltransferases, UPDATE, Female, PROTEIN STABILITY, LEUKEMIA
Abstract

Item does not contain fulltext Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Published
2017

7. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

Author

Mina Ryten, Sérgio B. Sousa, Richard H Scott, Estelle Chanudet, Glenn Anderson, Lionel Van Maldergem, Dagan Jenkins, Philip L. Beales, Krystyna H. Chrzanowska, James Docker, Jorge M. Saraiva, Philip Stanier, Gudrun E. Moore, Miho Ishida, Angela Barnicoat, Joaquim Sá, Martina Simandlova, Duangrurdee Wattanasirichaigoon, Guergana Tasseva, Jean E. Vance, and Alistair Calder

Subjects
Male, Fosfatidilserinas, Embryo, Nonmammalian, Adolescent, Nitrogenous Group Transferases, Molecular Sequence Data, Dwarfism, Phosphatidylserines, Biology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Missense mutation, Abnormalities, Multiple, Child, Gene, Cells, Cultured, Zebrafish, 030304 developmental biology, Transferases de Grupos Nitrogenados, Phosphatidylethanolamine, 0303 health sciences, Mutation, Deficiência Intelectual, Syndrome, Phosphatidylserine, Fibroblasts, Hyperostosis, medicine.disease, 3. Good health, chemistry, Craniotubular Hyperostosis, Female, Anomalias Congénitas Múltiplas, 030217 neurology & neurosurgery, Cutis laxa
Abstract

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

Published
2013

8. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Elliott H. Sherr, Edward Blair, Charles Marques Lourenço, James O'Sullivan, Imke Metz, Paul R. Kasher, Gabriela M. Baerlocher, Adeline Vanderver, David Cassiman, Himanshu Goel, Nicholas A. Fletcher, Patrick Ferreira, Patrick Revy, Emma Wakeling, Ram L. Kumar, Lieven Lagae, Christopher J. Kershaw, Pierre Landrieu, Andrea Whitney, Calvin Soh, Christine E. G. van Mol, Sakkubai Naidu, John H. Livingston, Geraldine Aubert, H. Stewart, Laurence C. Goosey, Liesbeth De Waele, Kristin W. Barañano, Rosalind J. Jefferson, Axel Panzer, Gerardine Quaghebeur, Raphael Schiffmann, Yanick J. Crow, Hilde Van Esch, Raymond T. O'Keefe, Jill E. Urquhart, Alan Fryer, Mathieu P Rodero, Alex J. Fay, Monika Haubitz, Andrea Berger, Johannes A. Buckard, Cheryl Hemingway, Angela Barnicoat, Sam Griffiths-Jones, Duccio Maria Cordelli, Imelda Hughes, Katrin Õunap, Graham D. Pavitt, Roberta Battini, Yoann Rose, Marjo S. van der Knaap, Sanjeev S. Bhaskar, John Stone, Gillian I. Rice, Marco Henneke, Kanaga R. Sinnathuray, Emma M. Jenkinson, Timothy J. Malpas, Simon G. Williams, Anthony Oojageer, Carolina Uggenti, Rosaline Caumes, Prab Prabhakar, Sarju G. Mehta, Janice E. Brunstrom-Hernandez, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Manchester [Manchester], Department of Medical Genetics, HMNC Brain Health, Other departments, Jenkinson, Emma M., Rodero, Mathieu P., Kasher, Paul R., Uggenti, Carolina, Oojageer, Anthony, Goosey, Laurence C., Rose, Yoann, Kershaw, Christopher J., Urquhart, Jill E., Williams, Simon G., Bhaskar, Sanjeev S., O'Sullivan, Jame, Baerlocher, Gabriela M., Haubitz, Monika, Aubert, Geraldine, Barañano, Kristin W., Barnicoat, Angela J., Battini, Roberta, Berger, Andrea, Blair, Edward M., Brunstrom-Hernandez, Janice E., Buckard, Johannes A., Cassiman, David M., Caumes, Rosaline, Cordelli, Duccio M., De Waele, Liesbeth M., Fay, Alexander J., Ferreira, Patrick, Fletcher, Nicholas A., Fryer, Alan E., Goel, Himanshu, Hemingway, Cheryl A., Henneke, Marco, Hughes, Imelda, Jefferson, Rosalind J., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre G., Lourenço, Charles M., Malpas, Timothy J., Mehta, Sarju G., Metz, Imke, Naidu, Sakkubai, Õunap, Katrin, Panzer, Axel, Prabhakar, Prab, Quaghebeur, Gerardine, Schiffmann, Raphael, Sherr, Elliott H., Sinnathuray, Kanaga R., Soh, Calvin, Stewart, Helen S., Stone, John, Van Esch, Hilde, Van Mol, Christine E. G., Vanderver, Adeline, Wakeling, Emma L., Whitney, Andrea, Pavitt, Graham D., Griffiths-Jones, Sam, Rice, Gillian I., Revy, Patrick, Van Der Knaap, Marjo S., Livingston, John H., O'Keefe, Raymond T., Crow, Yanick J., Pediatric surgery, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Ribosome biogenesis, medicine.disease_cause, Leukoencephalopathy, Leukoencephalopathie, Cohort Studies, 0302 clinical medicine, Leukoencephalopathies, Exome, Small nucleolar RNA, 610 Medicine & health, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Genome, Cysts, Calcinosis, Middle Aged, Phenotype, Child, Preschool, Calcinosi, Female, Sequence Analysis, Human, Adult, Adolescent, Biology, Chromosomes, Cell Line, 03 medical and health sciences, Young Adult, medicine, RNA, Small Nucleolar, Humans, Preschool, Gene, Small Nucleolar, Genome, Human, Pair 17, RNA, Infant, Sequence Analysis, DNA, DNA, Cerebral Small Vessel Diseases, Chromosomes, Human, Pair 17, medicine.disease, Cerebral Small Vessel Disease, 030104 developmental biology, Cyst, Cohort Studie, 030217 neurology & neurosurgery
Abstract

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2016

9. Intrafamilial Phenotypic Variability and Consequences of Non-Compliance with Treatment in Congenital Adrenal Hyperplasia and Congenital Hypothyroidism within a Single Family

Author

Abigail Atterbury, Nicola Improda, Angela Barnicoat, Nadia Schoenmakers, Senthil Senniappan, Caroline Ponmani, Krishna Chatterjee, and Mehul T. Dattani

Subjects
0301 basic medicine, Male, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, medicine.medical_specialty, endocrine system diseases, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, urologic and male genital diseases, Thyroglobulin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Non compliance, Congenital Hypothyroidism, Medicine, Adrenal adenoma, Humans, Congenital adrenal hyperplasia, Child, biology, Adrenal Hyperplasia, Congenital, business.industry, 21-Hydroxylase, medicine.disease, Phenotype, Congenital hypothyroidism, Pedigree, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), Mutation, biology.protein, Patient Compliance, Female, business, hormones, hormone substitutes, and hormone antagonists
Abstract

Background: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare. Case Series: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age. Conclusions: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control.

Published
2016

10. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation

Author

S. R. Phelps, J. Holland, J. Pointon, Angela Barnicoat, H.R. Middleton-Price, Kay E. Davies, L. Campbell, M.E. Pembrey, A. V. Flannery, Ben A. Oostra, Samantha J. L. Knight, Martin Bobrow, Mark C. Hirst, and Zoe Christodoulou

Subjects
Genetics, X Chromosome, Base Sequence, Chromosomal fragile site, Molecular Sequence Data, Gene Amplification, Locus (genetics), Chromosome Fragility, Biology, medicine.disease, Methylation, General Biochemistry, Genetics and Molecular Biology, Pedigree, Xq28, Fragile X syndrome, CpG site, Fragile X Syndrome, Intellectual Disability, medicine, Humans, Trinucleotide repeat expansion, X chromosome, Repetitive Sequences, Nucleic Acid
Abstract

We have cloned the fragile site FRAXE and demonstrate that individuals with this fragile site possess amplifications of a GCC repeat adjacent to a CpG island in Xq28 of the human X chromosome. Normal individuals have 6-25 copies of the GCC repeat, whereas mentally retarded, FRAXE-positive individuals have > 200 copies and also have methylation at the CpG island. This situation is similar to that seen at the FRAXA locus and is another example in which a trinucleotide repeat expansion is associated with a human genetic disorder. In contrast with the fragile X syndrome, the GCC repeat can expand or contract and is equally unstable when passed through the male or female line. These results also have implications for the understanding of chromosome fragility.

Published
2016

11. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Author

S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T

Subjects
Liver Cirrhosis, 2716 Genetics (clinical), meckelin, Ciliopathies, Joubert syndrome, Genotype, congenital hepatic fibrosis, coach syndrome, mks3, meckel syndrome, joubert syndrome, tmem67, TMEM67, Meckel syndrome, DNA Mutational Analysis, 610 Medicine & health, Biology, medicine.disease_cause, MKS3, COACH syndrome, Article, NO, 1311 Genetics, Nephronophthisis, Pregnancy, Prenatal Diagnosis, Genetics, medicine, COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67, Missense mutation, Humans, Abnormalities, Multiple, Genetics (clinical), Mutation, Cilium, Membrane Proteins, Kidney Diseases, Cystic, medicine.disease, Phenotype, 10036 Medical Clinic, Female
Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Published
2010

12. Transmitted duplication of 8p23.1–8p23.2 associated with speech delay, autism and learning difficulties

Author

Angela Barnicoat, John C K Barber, Ann Jackson, Viv K. Maloney, N. Simon Thomas, David J. Bunyan, Joanne Gilmore, Shuwen Huang, Mary Glancy, Sharon de Souza, and Rajan Vijeratnam

Subjects
Adult, Male, Candidate gene, MICROCEPHALIN, Mothers, Cell Cycle Proteins, Nerve Tissue Proteins, Biology, Article, Gene Duplication, Gene duplication, Genetics, medicine, Humans, Language Development Disorders, Multiplex ligation-dependent probe amplification, Autistic Disorder, education, In Situ Hybridization, Fluorescence, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Chromosomal inversion, education.field_of_study, Epilepsy, Learning Disabilities, Breakpoint, Chromosome Mapping, medicine.disease, Cytoskeletal Proteins, Mutagenesis, Insertional, Child, Preschool, Karyotyping, Speech delay, Autism, Female, medicine.symptom, Chromosomes, Human, Pair 8
Abstract

Duplications of distal 8p with and without significant clinical phenotypes have been reported and are often associated with an unusual degree of structural complexity. Here, we present a duplication of 8p23.1-8p23.2 ascertained in a child with speech delay and a diagnosis of ICD-10 autism. The same duplication was found in his mother who had epilepsy and learning problems. A combination of cytogenetic, FISH, microsatellite, MLPA and oaCGH analysis was used to show that the duplication extended over a minimum of 6.8 Mb between 3 539 893 and 10 323 426 bp. This interval contains 32 novel and 41 known genes, of which only microcephalin (MCPH1) is a plausible candidate gene for autism at present. The distal breakpoint of the duplicated region interrupts the CSMD1 gene in 8p23.2 and the medial breakpoint lies between the MSRA and RP1L1 genes in 8p23.1.An interchromosomal insertion between a normal and polymorphically inverted chromosome 8 is proposed to explain the origin of this duplication. Further mapped imbalances of distal 8p are needed to determine whether the autistic component of the phenotype in this family results from the cumulative imbalance of many genes or dosage imbalance of an individual susceptibility gene.

Published
2008

13. Erratum: Corrigendum: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Author

Esther Meyer, Manju A. Kurian, Sanjay Bhate, Jean-Pierre Lin, Agnel Praveen Joseph, Angela Barnicoat, F. Lucy Raymond, Jonathan R. Chubb, Niklas Darin, Shibalik Misra, Lucinda Carr, Joanne Ng, Deborah Morrogh, Julia Rankin, Henry Houlden, Erik-Jan Kamsteeg, Martin Smith, Patricia Limousin, Shane McKee, David Arkadir, Sarah Wiethoff, Hilla Ben-Pazi, Patrick Rump, Wui K. Chong, John M.E. Nichols, Michèl A.A.P. Willemsen, William A. Gahl, Gregory Peters, Detelina Grozeva, S Heales, Camilo Toro, André Reis, Shekeeb S Mohammed, Simon Pope, Deciphering Developmental Disorders Study, Adeline Ngoh, Joost Nicolai, Zvi Israel, Russell C. Dale, Nicholas W. Wood, Serena Barral, Niccolo E. Mencacci, Dagmar Wieczorek, Hardev Pall, Gidon Winter, Vasiliki Nakou, Peter D. Turnpenny, Prab Prabhakar, Kailash P. Bhatia, Alan Pittman, Margje Sinnema, Christopher Wragg, Keren J. Carss, Maya Topf, Amber Boys, Apostolos Papandreou, Hagai Bergman, Reeval Segel, Jane A. Hurst, Susan M. White, Nicholas Gutowski, A. Hills, Margaret Kaminska, Daniel E. Lumsden, Belén Pérez-Dueñas, Nicola Foulds, Kathryn J. Peall, Paul Gissen, Miriam S. Reuter, Magnus Nilsson, and Brian T. Wilson

Subjects
0301 basic medicine, Dystonia, Biology, medicine.disease, Bioinformatics, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Histone methyltransferase, Genetics, medicine, Gene, 030217 neurology & neurosurgery, Early onset
Abstract

Nat. Genet. 49, 223–237 (2017); published online 19 December 2016; corrected after print 20 April 2017 Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process.

Published
2017

14. Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1 : molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM

Author

Michael Parker, Maria Bitner-Glindzicz, William van’t Hoff, Sarah Rickard, Isabelle Russell-Eggitt, Angela Barnicoat, and Robin M. Winter

Subjects
Male, Genetic Linkage, DNA Mutational Analysis, Biology, Duane Retraction Syndrome, Exon, Genetic linkage, Duane syndrome, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Testing, Allele, Alleles, Polymorphism, Single-Stranded Conformational, Genetics (clinical), Sequence Deletion, Branchio-oto-renal syndrome, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Exons, medicine.disease, Phenotype, Genetic marker, Trans-Activators, Microsatellite, Female, Protein Tyrosine Phosphatases, Branchio-Oto-Renal Syndrome, Microsatellite Repeats
Abstract

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder involving hearing loss, branchial defects, ear pits and renal abnormalities. Oto-facio-cervical (OFC) syndrome is clinically similar to BOR syndrome, with clinical features in addition to those of BOR syndrome. Mutations in the EYA1 gene (localised to 8q13.3) account for nearly 70% of BOR syndrome cases exhibiting at least three of the major features. Small intragenic deletions of the 3' region of the gene have also been reported in patients with BOR syndrome. We have developed a fluorescent quantitative multiplex polymerase chain reaction for three 3' exons (7, 9 and 13) of the EYA1 gene. This dosage assay, combined with microsatellite marker analysis, has identified de novo deletions of the EYA1 gene and surrounding region in two patients with complex phenotypes involving features of BOR syndrome. One patient with OFC syndrome carried a large deletion of the EYA1 gene region, confirming that OFC syndrome is allelic with BOR syndrome. Microsatellite analysis has shown that comparison of the boundaries of this large deletion with other reported rearrangements of the region reduces the critical region for Duane syndrome (an eye movement disorder) to between markers D8S553 and D8S1797, a genetic distance of approximately 1 cM.

Published
2001

15. Disruption of the Bipartite Imprinting Center in a Family with Angelman Syndrome

Author

M. E. Pembrey, Bernhard Horsthemke, Karin Buiting, Sue Malcolm, Angela Barnicoat, and Christina Lich

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, Regulatory Sequences, Nucleic Acid, Biology, Germline, Nuclear Family, Genomic Imprinting, Exon, Germline mutation, Report, Angelman syndrome, Happy puppet syndrome, medicine, Genetics, Humans, Genetics(clinical), Imprinting (psychology), Germ-Line Mutation, Genetics (clinical), Chromosomal inversion, Chromosomes, Human, Pair 15, Base Sequence, Exons, medicine.disease, Pedigree, Chromosome Inversion, Female, Angelman Syndrome, Genomic imprinting, Prader-Willi Syndrome
Abstract

Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome (PWS). Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome (AS). So far, in all affected sibs with an imprinting defect, an inherited IC deletion was identified. We report on two sibs with AS who do not have an IC deletion but instead have a 1-1.5 Mb inversion separating the two IC elements. The inversion is transmitted silently through the male germline but impairs maternal imprinting after transmission through the female germline. Our findings suggest that the close proximity and/or the correct orientation of the two IC elements are/is necessary for the establishment of a maternal imprint.

Published
2001
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16. Analysis of KIT, SCF, and Initial Screening of SLUG in Patients with Piebaldism

Author

Kazuyoshi Fukai, Naoki Oiso, Robert Aquaron, Jacquely Riley, Jan Miertus, Tamio Suzuki, Katsuhiko Tsukamoto, Naoko Hosomi, Alexandra Santoro-Zea, Louise Wilson, Maria Bitner-Glindzicz, Atsushi Kato, Anthony J. Mancini, Hiroshi Ueda, Mauricio Camargo, Tomoko Murakami, Masamitsu Ishii, Angela Barnicoat, Joan F. Atkin, Maria Luisa Giovannucci-Uzielli, and Masako Mizoguchi

Subjects
Slug, Dermatology, Biology, SLUG, Biochemistry, Exon, medicine, Humans, Genetic Testing, Molecular Biology, Gene, Genetics, Stem Cell Factor, Piebaldism, Intron, tyrosine kinase, KIT, SCF, Single-strand conformation polymorphism, Cell Biology, medicine.disease, biology.organism_classification, Molecular biology, Proto-Oncogene Proteins c-kit, Protein kinase domain, Dominant white, Snail Family Transcription Factors, Transcription Factors
Abstract

Piebaldism is an autosomal dominant disorder, characterized by congenital leukoderma typically on the abdomen, knees, and forehead. Mice models for human piebaldism are the W dominant white spotting, the steel mice and the mice that are mutated for the slug gene. Human genes for these mice models were investigated in this study. Genomic DNAs of peripheral leukocytes were prepared from twenty-two patients with piebaldism. PCR-direct sequencing or screening by SSCP and subsequent sequencing of all of the exons and flanking introns of KIT, SCF (stem cell factor), and SLUG genes disclosed six pathological mutations only in KIT. Among them five were novel: 358delG, IVS3-2A>G, Q346X, H650L, and D792Y. His650 is located in the strand connecting the helix αC and the downstream β-sheet of the N-lobe of the active KIT kinase domain, the crystal fine structure of which was determined recently. Asp792 is situated in the center of the kinase active site of interdomain cleft between the N-lobe and the C-lobe. No pathological mutations were found in SCF or SLUG in our screening system. Analysis of mutations in the KIT kinase domain may offer an insight into the detailed functional role of this fascinating protein.

Published
2005

17. Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome

Author

Yoshiyuki Wakabayashi, Rupert Hinds, A.S. Knisely, Dorota Gliwicz, Björn Fischler, David Chitayat, Maria Gizewska, Eamonn R. Maher, Andrew R. Cullinane, Rachid Sougrat, Angela Barnicoat, Gulin Erdemir, Paul Gissen, Angels García-Cazorla, Deirdre Kelly, Kyung S. Song, Hanna Mandel, Beyhan Tüysüz, Jae Sung Ko, Jeong K. Seo, Dariusz Gruszfeld, Anna Straatman-Iwanowska, Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk Gastroenteroloji Hepatoloji ve Beslenme Bilim Dalı., and Erdemir, Gülin

Subjects
Male, medicine.medical_specialty, Child, preschool, Biology, medicine.disease_cause, Gastroenterology, Germline, Article, Germline mutation, Cholestasis, Renal tubular dysfunction, Internal medicine, Case report, medicine, Vesicular transport protein, Genetics, Humans, Neonatal cholestasis, Genetics (clinical), Arthrogryposis, Mutation, Arc (protein), Kidney diseases, Vps33b, Vesicular transport proteins, Genetics & heredity, Infant, Syndrome, Fibroblasts, Kidney disease, medicine.disease, ARC, Metabolism, Preschool child, Ultrastructure, Vesicular trafficking defect, Renal dysfunction, Gray Platelet Syndrome, Megakaryocytes, Blood Platelets, Fibroblast, medicine.symptom, VPS33B protein, Human, Ethnology
Abstract

Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a >50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in similar to 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC. Children's Liver Disease Foundation (CLDF) ARC syndrome association Children Living with Inherited Metabolic Diseases (CLIMB) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) United States Department of Health & Human Services National Institutes of Health (NIH) - USA Birmingham Children's Hospital Research Foundation (BCHRF)

Published
2009

18. Expanding CEP290 mutational spectrum in ciliopathies

Author

S. Halldorsson, Elliott H. Sherr, Susana Quijano-Roy, Gaetano Tortorella, Marc D'Hooghe, M. M. De Jong, J. Caldwell, Gian M. Ghiggeri, Josseline Kaplan, Christopher P. Bennett, S. Comu, Vincenzo Leuzzi, Anna Rajab, Mary Kay Koenig, Serap Teber, Barbara Scelsa, G. Marra, S. Kitsiou Tzeli, D. Petkovic, Alex E. Clark, Bruno Dallapiccola, P. Collignon, V. Sabolic Avramovska, Richard J. Leventer, Robert P. Cruse, Sabrina Signorini, Raoul C.M. Hennekam, Nicole I. Wolf, A. M. Laverda, Brunella Mancuso, Clotilde Lagier-Tourenne, Kathrin Ludwig, C. Moco, Ender Karaca, Amy Goldstein, Stefania Bigoni, L. I. Al Gazali, Laila Bastaki, Jean Messer, E. Del Giudice, M. Cazzagon, A. Permunian, C. Ae Kim, Edward Blair, M. Di Giacomo, E. DeMarco, Melissa Lees, Renato Borgatti, Marilena Briguglio, H. Raynes, Renaud Touraine, Andreas Zankl, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, S. Romano, Isabelle Perrault, Jane A. Hurst, Eamonn Sheridan, Kenton R. Holden, T. E. Gallager, P. De Lonlay, M. L. Di Sabato, Marina Michelson, Hülya Kayserili, Terry D. Sanger, Heike Philippi, Patrizia Accorsi, M. Silengo, Miriam Iannicelli, Lorena Travaglini, K. Dias, Gianluca Caridi, Loredana Boccone, J. Johannsdottir, R. De Vescovi, P. Ludvigsson, J. Hahn, Tania Attié-Bitach, Franco Stanzial, Silvia Battaglia, Francesco Brancati, Ghada M. H. Abdel-Salam, William B Dobyns, Enrico Bertini, Daria Riva, F. Benedicenti, Joseph G. Gleeson, Ryan D. Schubert, Roshan Koul, Kalpathy S. Krishnamoorthy, Luigina Spaccini, G. Uziel, Jean-Michel Rozet, M.A. Donati, Marzia Pollazzon, Sophie Audollent, Matloob Azam, Alex Magee, A. Adami, Ignacio Pascual-Castroviejo, Bernard Stuart, Rita Fischetto, Darryl C. De Vivo, Christopher A. Walsh, Asma A. Al-Tawari, Carla Uggetti, Alessandra Ferlini, Atıl Yüksel, Enza Maria Valente, Agnese Suppiej, Faustina Lalatta, Lucio Giordano, Maria Roberta Cilio, Bernard L. Maria, Trudy McKanna, S. Sigaudy, L. Demerleir, Carmelo Salpietro, Henry Sanchez, Bruria Ben-Zeev, A. Pessagno, Elisa Fazzi, J. Milisa, Shubha R. Phadke, D. Greco, Dominika Swistun, Yves Sznajer, B. Rodriguez, Silvana Briuglia, V. Udani, Francesca Faravelli, Maha S. Zaki, S. Bernes, Maria Teresa Divizia, C. Daugherty, David G. Brooks, Clara Barbot, László Sztriha, C. Donahue, Wendy K. Chung, Dean Sarco, Pierangela Castorina, Petter Strømme, Pasquale Parisi, Andreas R. Janecke, Roberta Battini, L. Martorell Sampol, M. Akcakus, Angela Barnicoat, Jerlyn C Tolentino, Dorit Lev, A. Seward, Banu Anlar, Corrado Romano, D. Nicholl, A. Moreira, Alice Abdel-Aleem, Padraic Grattan-Smith, C. G. Woods, Gustavo Maegawa, Alessandro Simonati, Kathryn J. Swoboda, David Viskochil, Luciana Rigoli, R. Van Coster, André Mégarbané, Pediatric surgery, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatric Genetics, Travaglini, L., Brancati, F., Attie Bitach, T., Audollent, S., Bertini, E., Kaplan, J., Perrault, I., Iannicelli, M., Mancuso, B., Rigoli, L., Rozet, J. M., Swistun, D., Tolentino, J., Dallapiccola, B., Gleeson, J. G., Valente, E. M., The International JSRD Study, Group, and DEL GIUDICE, Ennio

Subjects
genetic structures, DNA Mutational Analysis, Cell Cycle Proteins, Biology, Ciliopathies, cep290, Article, Joubert syndrome, meckel syndrome, 03 medical and health sciences, Exon, Fetus, 0302 clinical medicine, Bardet–Biedl syndrome, Joubert syndrome and related disorders, Meckel syndrome, CEP290, genomic rearrangement, Antigens, Neoplasm, Nephronophthisis, Genetics, medicine, joubert syndrome and related disorders, Humans, Abnormalities, Multiple, ciliopathy, Cilia, Genetic Testing, RNA, Messenger, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, Genomic rearrangement, Syndrome, medicine.disease, eye diseases, Neoplasm Proteins, Cytoskeletal Proteins, RPGRIP1L, Female, sense organs, Gene Deletion, 030217 neurology & neurosurgery
Abstract

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/ MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C -terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Published
2009

19. New KIT mutations in patients with piebaldism

Author

Amy S. Paller, Cheryl Garganta, Angela Barnicoat, Francis Poppelaars, Robert Aquaron, Naoki Oiso, Masamitsu Ishii, Tomoko Murakami, Kazuyoshi Fukai, Naoko Hosomi, and Atsushi Kato

Subjects
Adult, Male, Genotype, Leukoderma, Mutation, Missense, Dermatology, Biology, medicine.disease_cause, Biochemistry, Polymerase Chain Reaction, Frameshift mutation, medicine, Missense mutation, Humans, Frameshift Mutation, Molecular Biology, Genetics, Mutation, Piebaldism, medicine.disease, Phenotype, Pedigree, genomic DNA, Proto-Oncogene Proteins c-kit, Child, Preschool, Female
Abstract

Background : Piebaldism is an autosomal dominantly inherited disorder characterized by congenital leukoderma, typically on the forehead, abdomen, and knees. The leukoderma is usually stable throughout life. KIT mutations have been demonstrated in about 75% of patients with piebaldism. Objectives : To identify KIT mutations of the family with piebaldism and examine genotype-phenotype correlations in this disorder. Methods : PCR-direct-sequencing technique using genomic DNA from peripheral leukocytes. Results : We have studied 10 individuals within six piebaldism families and able to identify six novel mutations in the KIT gene in patients with piebaldism. These include four frameshift mutations: 142delG, 1768–1769delAG, 2139delC, 2246–2249delAAAG, and two missense mutations: M541L, Y870C. Conclusions : These six new mutations are associated with phenotypes that are well in accordance with our knowledge of genotype-phenotype correlations in KIT .

Published
2003

20. A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp

Author

Angela Barnicoat, C. Lich, S. Cottrell, Karin Buiting, and B. Horsthemke

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Centromere, Molecular Sequence Data, Locus (genetics), Biology, Genomic Imprinting, Gene mapping, Angelman syndrome, Happy puppet syndrome, Genetics, medicine, Humans, Imprinting (psychology), Genetics (clinical), Chromosomes, Human, Pair 15, Base Sequence, nutritional and metabolic diseases, Chromosome Breakage, medicine.disease, Physical Chromosome Mapping, Human genetics, Blotting, Southern, Congenital disease, Angelman Syndrome, Gene Deletion
Abstract

Imprinting on human chromosome 15q11-q13 is controlled by a bipartite imprinting center (IC) that maps to the SNRPN locus. Deletions of the IC result in an imprinting defect and Prader-Willi syndrome or Angelman syndrome (AS). We have now identified a 5-kb IC deletion in an English AS patient (AS-LO); this represents the smallest microdeletion found in AS and narrows down the shortest region of deletion overlap to 880 bp.

Published
2000

21. Clinical and genetic heterogeneity in Meckel syndrome

Author

Angela Barnicoat, Riitta Salonen, Steve Gould, Albert Schinzel, Robin M. Winter, H. Meusburger, Paulina Paavola, Romano Tenconi, Patricia A. Boyd, Alessandra Baumer, and Leena Peltonen

Subjects
Liver Cirrhosis, Male, Genetic Linkage, Locus (genetics), Biology, 03 medical and health sciences, Locus heterogeneity, Pregnancy, Genetics, medicine, Humans, Abnormalities, Multiple, Neural Tube Defects, Allele, Meckel syndrome, Genetics (clinical), Alleles, 030304 developmental biology, Meckel-Gruber Syndrome, 0303 health sciences, Polycystic Kidney Diseases, Polydactyly, urogenital system, Genetic heterogeneity, 030305 genetics & heredity, Haplotype, Infant, Newborn, DNA, Syndrome, medicine.disease, 3. Good health, Pedigree, Phenotype, Female, Lod Score
Abstract

Meckel syndrome (MKS) is a lethal malformation syndrome characterised by posterior meningoencephalocele, polycystic kidneys, fibrotic changes of the liver, and polydactyly. We have previously shown a linkage to chromosome 17q in 17 Finnish Meckel families. In this study we have analysed one Italian, one Austrian (of Turkish origin) and three British MKS families (Caucasian, Pakistani, and Bangladeshi families) for linkage to the MKS locus on chromosome 17q22–q24. We did not observe co-segregation of the disease and marker haplotypes in the Austrian family or in the three British families, of which two represented classical MKS and one a slightly atypical MKS phenotype with longer survival of the patient. In the Italian family the affected and non-affected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. These results suggest locus heterogeneity in Meckel syndrome – a feature previously suspected based on the highly variable clinical phenotype.

Published
1998

26. The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE

Author

M. Daker, K.E. Davies, Q Wang, Angela Barnicoat, V. J. Buckle, Martin Bobrow, Mark C. Hirst, and G A Flynn

Subjects
Adult, Genetic Markers, Male, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, Adolescent, Biology, Fragility, Gene mapping, Genetics, medicine, Humans, Molecular Biology, Genetics (clinical), X chromosome, In Situ Hybridization, Fluorescence, Chromosomal fragile site, Chromosome Fragile Sites, Chromosome Fragility, Infant, General Medicine, medicine.disease, FMR1, Chromatin, Pedigree, Fragile X syndrome, Fragile X Syndrome, Mutation (genetic algorithm), Female
Abstract

FRAXA is unique amongst fragile sites in that it is intimately involved with a specific clinical phenotype, the fragile X syndrome. Whilst the majority of fragile X individuals have been found to have a characteristic mutation in the FMR1 gene, a small proportion of individuals exhibiting fragility have no such mutation. Investigation of the site of chromosome fragility in these FMR1 mutation negative, fragile X site positive individuals, has identified a second site of fragility, FRAXE. However, the presence of FRAXE has not explained all such cases. Here we describe a fragile X site positive, FMR1 mutation negative family, in which chromosome fragility is not due to the FRAXA or FRAXE but is due to a third site designated FRAXF. Using fluorescent in situ hybridisation (FISH) this site is shown to lie over 1Mb distal to FRAXA. The identification of a third fragile site in this small region of the X chromosome provides an opportunity to extend our studies of the molecular nature of chromosome fragility.

Published
1993

27. Screening for fragile X syndrome: a model for genetic disorders?

Author

Angela Barnicoat

Subjects
Genetics, education.field_of_study, Chromosomal fragile site, Population, General Engineering, General Medicine, Biology, Early Therapy, medicine.disease, Fragile X syndrome, Dynamic mutation, medicine, General Earth and Planetary Sciences, education, Asymptomatic carrier, X-linked recessive inheritance, X chromosome, General Environmental Science
Abstract

The fragile X syndrome is often cited as the commonest inherited cause of mental handicap. It was described after the finding that a fragile site at the distal end of the X chromosome was associated with mental handicap. The X linked inheritance pattern is atypical; female carriers may show some features, and males may also occasionally be asymptomatic carriers. Fragile X syndrome was the first of an increasing number of neurological genetic conditions in which a dynamic mutation of a triplet repeat was identified, where instability between generations explained the unusual inheritance pattern.1 The documentation of the molecular pathology in fragile X allowed confirmation of carrier status in both male and female family members. The growth in understanding of the condition led to early calls for screening,2 proposed both to implement early therapy and to reduce the birth prevalence. Several approaches to screening are possible, broadly divided into either case finding with cascade screening (of relatives at risk in the extended family) or population …

Published
1997

28. Regarding the Consensus Statement on 21-Hydroxylase Deficiency from the Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology

Author

Duncan T. Wilcox, Christopher Woodhouse, L.-M. Liao, Patrick G. Duffy, Richard Stanhope, Catherine L Minto, Peter Cuckow, Naomi S. Crouch, P.G. Ransley, Ieuan Hughes, Gerard S. Conway, Peter C. Hindmarsh, Mehul T. Dattani, Les Perry, Imran Mushtaq, John Achermann, Sarah M. Creighton, Angela Barnicoat, and Caroline Brain

Subjects
Male, medicine.medical_specialty, Consensus, Statement (logic), Pediatric endocrinology, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Pediatrics, Biochemistry, Endocrinology, Internal medicine, medicine, Humans, Endocrine system, Congenital adrenal hyperplasia, Genitalia, Child, education, Societies, Medical, education.field_of_study, Adrenal Hyperplasia, Congenital, biology, business.industry, Biochemistry (medical), 21-Hydroxylase, Gender Identity, medicine.disease, Europe, Paediatric endocrinology, biology.protein, Female, Steroid 21-Hydroxylase, business, Developed country
Abstract

Despite over 50 yr of experience with steroid replacement therapy the management of congenital adrenal hyperplasia (CAH) remains difficult and clinical practice varies substantially throughout the world. To consider the evidence for best practice to formulate management guidelines and to consider innovative therapies The Lawson Wilkins Pediatric Endocrine Society (LWPES) and The European Society for Pediatric Endocrinology (ESPE) convened a meeting in Gloucester MA March 14-17 2002. The 40 participating physicians psychologists scientists and surgeons from 12 countries on 4 continents agreed with the following consensus statement; this statement is concerned exclusively with CAH caused by 21-hydroxylase deficiency and does not address the other rarer forms of CAH. (excerpt)

Published
2003

29. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Sau Wai Cheung, Usha Kini, Han G. Brunner, Rolph Pfundt, Ronald Roepman, V. Reid Sutton, Lachlan A. Jolly, Jozef Gecz, Helena Malmgren, Deepti Domingo, Brooke L. Latour, Ka Man Wu, Emma Hobson, Maaike Vreeburg, Christian Gilissen, Carlo M. Marcelis, Bruno Reversade, Pilar L. Magoulas, Tjitske Kleefstra, Angela Barnicoat, Sue Price, Vasilios Zachariadis, Margot R.F. Reijnders, Hermine E. Veenstra-Knol, Jiin Ying Lim, Conny M. A. van Ravenswaaij-Arts, Nicola S. Cooper, Frank J. Probst, G. M. S. Mancini, Arja Harila-Saari, Alice S. Brooks, Ann Nordgren, Britt-Marie Anderlid, Stephen A. Wood, Zornitza Stark, Julie Vogt, Angeline Hwei Meeng Lai, Clinical Genetics, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Center for Reproductive Medicine, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
0301 basic medicine, Developmental Disabilities, Choanal atresia, medicine.disease_cause, FAT-FACETS GENE, BETA-CATENIN, 0302 clinical medicine, Genes, X-Linked, X Chromosome Inactivation, Genetics(clinical), 10. No inequality, Child, Genetics (clinical), Genetics, Mutation, Polydactyly, Cilium, Phenotype, Child, Preschool, Female, DEUBIQUITYLATING ENZYME, medicine.symptom, Ubiquitin Thiolesterase, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, Adolescent, DISORDERS, Molecular Sequence Data, INTERACTS, Biology, Short stature, Choanal Atresia, 03 medical and health sciences, Young Adult, X-CHROMOSOME INACTIVATION, Internal medicine, Intellectual Disability, Report, medicine, Humans, Genetic Testing, LINKED INTELLECTUAL DISABILITY, Loss function, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, medicine.disease, Ciliopathy, DEUBIQUITINATING ENZYME, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Endocrinology, FAM/USP9X, EXPRESSION ANALYSIS, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 167699.pdf (Publisher’s version ) (Open Access) Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

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30. 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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