Human Mutation

Cover image for Vol. 35 Issue 4

April 2014

Volume 35, Issue 4

Pages i–v, 395–512

  1. Content

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
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      Contents (pages i–iii)

      Version of Record online: 17 MAR 2014 | DOI: 10.1002/humu.22546

  2. In This Issue

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. You have free access to this content
      The Challenge of Genomic Medicine (page v)

      Elizabeth C. Chao

      Version of Record online: 17 MAR 2014 | DOI: 10.1002/humu.22407

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  3. Reviews

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. Prediction of the Repeat Domain Structures and Impact of Parkinsonism-Associated Variations on Structure and Function of all Functional Domains of Leucine-Rich Repeat Kinase 2 (LRRK2) (pages 395–412)

      Ryan D. Mills, Terrence D. Mulhern, Fei Liu, Janetta G. Culvenor and Heung-Chin Cheng

      Version of Record online: 24 FEB 2014 | DOI: 10.1002/humu.22515

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      This manuscript describes the structural models of all functional domains of Leucine-rich repeat kinase 2 (LRRK2). The models allow prediction of (i) the motifs essential for protein-protein interactions and/or catalysis in LRRK2, and (ii) the possible impact of the familial Parkinson's disease-associated mutations on the neurotoxic activity of LRRK2.

    2. Integrating Massively Parallel Sequencing into Diagnostic Workflows and Managing the Annotation and Clinical Interpretation Challenge (pages 413–423)

      Karin S. Kassahn, Hamish S. Scott and Melody C. Caramins

      Version of Record online: 6 MAR 2014 | DOI: 10.1002/humu.22525

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      Massively parallel sequencing (MPS) has become a powerful tool for the clinical management of patients with applications in diagnosis, guidance of treatment, prediction of drug response, and carrier screening. A considerable challenge for the clinical implementation of these technologies is the management of the vast amount of sequence data generated, in particular the annotation and clinical interpretation of genomic variants. Here, we describe annotation steps that can be automated and common strategies employed for variant prioritization. The lines between diagnostics and research start to blur as each patient becomes a study for new disease variants in its own right (“personal genomics”).

  4. Mutation Updates

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. Expanding the Mutational Spectrum of CRLF1 in Crisponi/CISS1 Syndrome (pages 424–433)

      Roberta Piras, Francesca Chiappe, Ilaria La Torraca, Insa Buers, Gianluca Usala, Andrea Angius, Mustafa Ali Akin, Lina Basel-Vanagaite, Francesco Benedicenti, Elisabetta Chiodin, Osama El Assy, Michal Feingold-Zadok, Javier Guibert, Benjamin Kamien, Çiğdem Seher Kasapkara, Esra Kılıç, Koray Boduroğlu, Selim Kurtoglu, Adnan Y Manzur, Eray Esra Onal, Enrica Paderi, Carmen Herrero Roche, Leyla Tümer, Sezin Unal, Gülen Eda Utine, Giovanni Zanda, Andreas Zankl, Giuseppe Zampino, Giangiorgio Crisponi, Laura Crisponi and Frank Rutsch

      Version of Record online: 6 MAR 2014 | DOI: 10.1002/humu.22522

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      Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 Syndrome Mutations in the CRLF1 gene are responsible for Crisponi/Cold Induced Sweating Syndrome Type 1 (CS/CISS1), a rare autosomal-recessive disorder characterized by four distinct features, such as hyperthermia and feeding difficulties in the neonatal period, scoliosis, and cold-induced sweating in the evolutive period. In this study we expanded the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants in 56 patients from 47 families. The highest prevalence is found in Sardinia, Turkey and Spain.

  5. Informatics

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. You have full text access to this OnlineOpen article
      Robust Diagnostic Genetic Testing Using Solution Capture Enrichment and a Novel Variant-Filtering Interface (pages 434–441)

      Christopher M. Watson, Laura A. Crinnion, Joanne E. Morgan, Sally M. Harrison, Christine P. Diggle, Julian Adlard, Helen A. Lindsay, Nick Camm, Ruth Charlton, Eamonn Sheridan, David T. Bonthron, Graham R. Taylor and Ian M. Carr

      Version of Record online: 17 MAR 2014 | DOI: 10.1002/humu.22490

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      We present two programs, AgileExomeFilter and AgilePindelFilter, which enable clinical scientists to rapidly and efficiently filter variants from next generation sequencing data. Using these tools a high diagnostic yield (42%) was obtained in a cohort of 24 primary ciliary dyskinesia (PCD) patients that underwent targeted exome analysis. Autozygosity mapping in the mutation negative cases revealed a homozygous truncating mutation in DNAH8, a presumptive new PCD gene.

  6. Brief Reports

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    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. A Novel Splice Site Mutation in the Noncoding Region of BRCA2: Implications for Fanconi Anemia and Familial Breast Cancer Diagnostics (pages 442–446)

      Janine L. Bakker, Eswary Thirthagiri, Saskia E. van Mil, Muriel A. Adank, Hideyuki Ikeda, Henk M. W. Verheul, Hanne Meijers-Heijboer, Johan P. de Winter, Shyam K. Sharan and Quinten Waisfisz

      Version of Record online: 15 FEB 2014 | DOI: 10.1002/humu.22505

    2. TBC1D7 Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease (pages 447–451)

      Ali Abdullah Alfaiz, Lucia Micale, Barbara Mandriani, Bartolomeo Augello, Maria Teresa Pellico, Jacqueline Chrast, Ioannis Xenarios, Leopoldo Zelante, Giuseppe Merla and Alexandre Reymond

      Version of Record online: 17 MAR 2014 | DOI: 10.1002/humu.22529

  7. Research Articles

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies (pages 452–461)

      Ping Li, Peter Meinke, Le Thi Thanh Huong, Manfred Wehnert and Angelika A. Noegel

      Version of Record online: 13 JAN 2014 | DOI: 10.1002/humu.22504

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      We characterize fibroblasts from muscular dystrophy patients with mutations in the nuclear proteins emerin and LAP2alpha in combination with SUN1 mutations and identify changes in cell size, proliferation, centrosome positioning, senescence, and cell migration. At the biochemical level the SUN1 mutations affect the interaction with lamin A/C and emerin. This affects the tested cellular properties. We conclude that the presence of two faulty nuclear genes associated with maintaining nuclear envelope structure and function produces both a more severe cellular and clinical phenotype.

    2. Thirteen New Patients with Guanidinoacetate Methyltransferase Deficiency and Functional Characterization of Nineteen Novel Missense Variants in the GAMT Gene (pages 462–469)

      Saadet Mercimek-Mahmutoglu, Joseph Ndika, Warsha Kanhai, Thierry Billette de Villemeur, David Cheillan, Ernst Christensen, Nathalie Dorison, Vickie Hannig, Yvonne Hendriks, Floris C. Hofstede, Laurence Lion-Francois, Allan M. Lund, Helen Mundy, Gaele Pitelet, Miquel Raspall-Chaure, Jessica A. Scott-Schwoerer, Katalin Szakszon, Vassili Valayannopoulos, Monique Williams and Gajja S. Salomons

      Version of Record online: 6 MAR 2014 | DOI: 10.1002/humu.22511

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      We report 13 new patients with GAMT deficiency, six novel mutations in the GAMT gene and functional analysis of 19 missense variants by side-directed mutagenesis (SDM). By software modelling, p.Pro8Thr and p.Tyr27His were predicted to be pathogenic, but functional analysis showed non-pathogenicity and p.Arg208Pro predicted not to be pathogenic, but was pathogenic by functional analysis. These findings prove that functional characterization of missense variants in the GAMT gene is essential for the confirmation of the pathogenicity of the missense variants.

    3. Two Novel Mutations in the BCKDK (Branched-Chain Keto-Acid Dehydrogenase Kinase) Gene Are Responsible for a Neurobehavioral Deficit in Two Pediatric Unrelated Patients (pages 470–477)

      Angels García-Cazorla, Alfonso Oyarzabal, Joana Fort, Concepción Robles, Esperanza Castejón, Pedro Ruiz-Sala, Susanna Bodoy, Begoña Merinero, Anna Lopez-Sala, Joaquín Dopazo, Virginia Nunes, Magdalena Ugarte, Rafael Artuch, Manuel Palacín, Pilar Rodríguez-Pombo, Working Group: (Patricia Alcaide, Rosa Navarrete, Paloma Sanz, Mariona Font-Llitjós, Ma Antonia Vilaseca, Aida Ormaizabal, Anna Pristoupilova and Sergi Beltran Agulló)

      Version of Record online: 5 MAR 2014 | DOI: 10.1002/humu.22513

    4. Delineation of EFTUD2 Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients (pages 478–485)

      Daphné Lehalle, Christopher T. Gordon, Myriam Oufadem, Géraldine Goudefroye, Lucile Boutaud, Jean-Luc Alessandri, Neus Baena, Geneviève Baujat, Clarisse Baumann, Odile Boute-Benejean, Roseline Caumes, Charles Decaestecker, Dominique Gaillard, Alice Goldenberg, Marie Gonzales, Muriel Holder-Espinasse, Marie-Line Jacquemont, Didier Lacombe, Sylvie Manouvrier-Hanu, Sandrine Marlin, Michèle Mathieu-Dramard, Gilles Morin, Laurent Pasquier, Florence Petit, Marlène Rio, Robert Smigiel, Christel Thauvin-Robinet, Alexandre Vasiljevic, Alain Verloes, Valérie Malan, Arnold Munnich, Loïc de Pontual, Michel Vekemans, Stanislas Lyonnet, Tania Attié-Bitach and Jeanne Amiel

      Version of Record online: 5 MAR 2014 | DOI: 10.1002/humu.22517

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      We have delineated the clinical spectrum of Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) in a series of 36 patients with mutations in EFTUD2, which encodes a component of the spliceosome. Despite high phenotypic variability amongst MFDGA patients, a characteristic facial gestalt provides the most useful diagnostic handle.

    5. Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene (pages 486–496)

      Martin de Boer, Karin van Leeuwen, Judy Geissler, Corry M. Weemaes, Timo K. van den Berg, Taco W. Kuijpers, Adilia Warris and Dirk Roos

      Version of Record online: 24 FEB 2014 | DOI: 10.1002/humu.22519

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      Usually, LINE-1 elements insert their own RNA or that of Alu elements. We report insertion of mRNA from the TMF1 gene (chromosome 3) into the CYBB gene (X chromosome). The inserted TMF1 mRNA was incomplete and partly exonized. Part of it was included in the CYBB mRNA as an extra exon, with a premature stopcodon. The retrotransposition took place in the early fetal development of the mother of the patient.

    6. Functional Mutation Analysis Provides Evidence for a Role of REEP1 in Lipid Droplet Biology (pages 497–504)

      Julia Falk, Magdalena Rohde, Mohamed M. Bekhite, Sophie Neugebauer, Peter Hemmerich, Michael Kiehntopf, Thomas Deufel, Christian A. Hübner and Christian Beetz

      Version of Record online: 5 MAR 2014 | DOI: 10.1002/humu.22521

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      The axonopathy-associated protein REEP1 has been considered to be specific to the endoplasmic reticulum (ER) [A]. We found that various ways of interfering with integrity of the hydrophobic N-terminus result in exclusive localization to lipid droplets (LDs) [B]. REEP1 may thus perform a critical function at the neuronal ER-LD interface [C].

  8. Meeting Reports

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
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  9. Errata

    1. Top of page
    2. Content
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Informatics
    7. Brief Reports
    8. Research Articles
    9. Meeting Reports
    10. Errata
    1. You have free access to this content
      Molecular Characterization and Cancer Risk Associated with BRCA1 and BRCA2 Splice Site Variants Identified in Multiple-Case Breast Cancer Families (page 511)

      A. A. Tesoriero, E. M. Wong, M. A. Jenkins, J. L. Hopper, , kConFab, M. A. Brown, G. Chenevix-Trench, A. B. Spurdle and M. C. Southey

      Version of Record online: 6 MAR 2014 | DOI: 10.1002/humu.22526

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      A Recurrent Loss-of-Function Alanyl-tRNA Synthetase (AARS) Mutation in Patients with Charcot-Marie-Tooth Disease Type 2N (CMT2N) (page 512)

      Heather M. McLaughlin, Reiko Sakaguchi, William Giblin, NIH Intramural Sequencing Center, Thomas E. Wilson, Leslie Biesecker, James R. Lupski, Kevin Talbot, Jeffery M. Vance, Stephan Züchner, Yi-Chung Lee, Marina Kennerson, Ya-Ming Hou, Garth Nicholson and Anthony Antonellis

      Version of Record online: 18 FEB 2014 | DOI: 10.1002/humu.22527

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