Human Mutation

Cover image for Human Mutation

April 2013

Volume 34, Issue 4

Pages v–v, 539–667

  1. Features

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
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  2. Informatics

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. You have free access to this content
      AudioGene: Predicting Hearing Loss Genotypes from Phenotypes to Guide Genetic Screening (pages 539–545)

      Kyle R. Taylor, Adam P. DeLuca, A. Eliot Shearer, Michael S. Hildebrand, E. Ann Black-Ziegelbein, V. Nikhil Anand, Christina M. Sloan, Robert W. Eppsteiner, Todd E. Scheetz, Patrick L. M. Huygen, Richard J. H. Smith, Terry A. Braun and Thomas L. Casavant

      Article first published online: 19 FEB 2013 | DOI: 10.1002/humu.22268

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      This article describes an accurate method for the diagnosis of mutations in genes, with pseudogene copies, at the single cell level for preimplantation genetic diagnostic purposes. The method is sensitive enough to detect germline mosaicism in single gametes.

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      RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs (pages 546–556)

      Radhakrishnan Sabarinathan, Hakim Tafer, Stefan E. Seemann, Ivo L. Hofacker, Peter F. Stadler and Jan Gorodkin

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22273

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      Structural characteristics are essential for the functioning of many non-coding RNAs and cis-regulatory elements of mRNAs. Predictions of the significance of sequence variants on structural effects were made using RNAsnp on a dataset of 30 known SNPs reported to have a structural effect. The four experimentally validated SNPs were correctly predicted with this application (p-value < 0.1).

      Corrected by:

      Erratum: RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs

      Vol. 34, Issue 6, 925, Article first published online: 9 APR 2013

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      Prediction of Mutant mRNA Splice Isoforms by Information Theory-Based Exon Definition (pages 557–565)

      Eliseos J. Mucaki, Ben C. Shirley and Peter K. Rogan

      Article first published online: 21 FEB 2013 | DOI: 10.1002/humu.22277

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      Cryptic and exon skipping isoforms in mRNA produced by splicing mutations are predicted from the combined information contents and distribution of the splice sites defining these exons. Predictions of splicing mutations were highly concordant with published expression data. In silico exon definition analysis will contribute to streamlining assessment of abnormal and normal splice isoforms resulting from mutations.

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      PhenoDB: A New Web-Based Tool for the Collection, Storage, and Analysis of Phenotypic Features (pages 566–571)

      Ada Hamosh, Nara Sobreira, Julie Hoover-Fong, V. Reid Sutton, Corinne Boehm, François Schiettecatte and David Valle

      Article first published online: 4 MAR 2013 | DOI: 10.1002/humu.22283

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      PhenoDB (http://phenodb.net) is a secure web-based tool for the collection, storage, and analysis of standardized phenotypic features as well as clinical, pedigree and genomic information. The 2900 features are mapped to the Human Phenotype Ontology and other terminologies to ensure maximum interoperability. While developed for use in the Centers for Mendelian Genomics project, it may be useful for any clinical or research project undertaking whole exome or whole genome sequencing and as such is freely available

  3. Rapid Communications

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing (pages 572–577)

      Joakim Klar, Maria Sobol, Atle Melberg, Katrin Mäbert, Adam Ameur, Anna C.V. Johansson, Lars Feuk, Miriam Entesarian, Hanna Örlén, Olivera Casar-Borota and Niklas Dahl

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22282

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      A heterozygous missense mutation in the gene encoding the RNA binding protein TIA1 causes Welander distal myopathy (WDM). WDM patients show increased SMN2 exon 7 skipping in skeletal muscle as well as an accumulation of TIA1 and stress granule proteins in intracellular vacuoles. The age of the TIA1 mutation is calculated to 1050 years from the conserved chromosome 2p13 haplotype.

  4. Brief Reports

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. A Homozygous Frameshift Mutation in the HOXC13 Gene Underlies Pure Hair and Nail Ectodermal Dysplasia in a Syrian Family (pages 578–581)

      Muhammad Farooq, Mazen Kurban, Atsushi Fujimoto, Hiroki Fujikawa, Ossama Abbas, Georges Nemer, Jessica Saliba, Rima Sleiman, Mona Tofaili, Abdul-Ghani Kibbi, Masaaki Ito and Yutaka Shimomura

      Article first published online: 5 MAR 2013 | DOI: 10.1002/humu.22271

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      In this study, we analyzed a consanguineous Syrian family with an affected girl with pure hair and nail ectodermal dysplasia, which is a rare genetic disorder characterized by alopecia and nail dystrophy since birth. Linkage studies and direct sequencing analysis led to the identification of a homozygous frameshift mutation (c.355delC; p.Leu119Trpfs*20) in the HOXC13 gene of the patient. In vitro studies in cultured cells demonstrated loss of function of the mutant HOXC13 protein.

    2. A Deletion Mutation in TMEM38B Associated with Autosomal Recessive Osteogenesis Imperfecta (pages 582–586)

      Michael Volodarsky, Barak Markus, Idan Cohen, Orna Staretz-Chacham, Hagit Flusser, Daniella Landau, Ilan Shelef, Yshaia Langer and Ohad S. Birk

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22274

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      We demonstrate through homozygosity mapping and whole exome seuquencing that autosomal recessive osteogensis imperfecta (OI) type IV is associated with a homozygous deletion mutation of exon 4 of TMEM38B. TMEM38B encodes TRIC-B, a ubiquitous component of TRIC, a monovalent cation-specific channel involved in Ca2+ release from intracellular stores that has been shown to act in cell differentiation.

  5. Research Articles

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. Genotype–Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2 (pages 587–594)

      Dorothea Bornholdt, T. Prescott Atkinson, Bakar Bouadjar, Benoit Catteau, Helen Cox, Deepthi De Silva, Judith Fischer, Chalukya N. Gunasekera, Smaïl Hadj-Rabia, Rudolf Happle, Muriel Holder-Espinasse, Elke Kaminski, Arne König, André Mégarbané, Hala Mégarbané, Ulrike Neidel, Frank Oeffner, Vinzenz Oji, Amy Theos, Heiko Traupe, Anders Vahlquist, Bregje W. van Bon, Marie Virtanen and Karl-Heinz Grzeschik

      Article first published online: 8 MAR 2013 | DOI: 10.1002/humu.22275

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      Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, or the X-linked form of Olmsted Syndrome.

    2. Genome-Wide Allelic Methylation Analysis Reveals Disease-Specific Susceptibility to Multiple Methylation Defects in Imprinting Syndromes (pages 595–602)

      Franck Court, Alex Martin-Trujillo, Valeria Romanelli, Intza Garin, Isabel Iglesias-Platas, Ira Salafsky, Miriam Guitart, Guiomar Perez de Nanclares, Pablo Lapunzina and David Monk

      Article first published online: 19 FEB 2013 | DOI: 10.1002/humu.22276

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      Genomic imprinting is the parent-of-origin specific allelic transcriptional silencing observed in mammals. Abnormal methylation at imprinted loci is associated with various imprinting syndromes. We analysed of 26 imprinted DMRs and identified multi-locus hypomethyaltion in numerous BWS, TNDM and PHP-1B patients, and an individual with SRS, but not in PWS or AS patients. A mutation screen of ZFP57, NLRP2, NLRP7 and KHDC3L revealed only one causative change, a ZFP57 1bp deletion, in a TNDM patient with multiple-hypomethylation.

    3. Novel Germline GJA5/Connexin40 Mutations Associated with Lone Atrial Fibrillation Impair Gap Junctional Intercellular Communication (pages 603–609)

      Yiguo Sun, Yi-Qing Yang, Xiang-Qun Gong, Xin-Hua Wang, Ruo-Gu Li, Hong-Wei Tan, Xu Liu, Wei-Yi Fang and Donglin Bai

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22278

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      We characterized the cellular and molecular mechanisms of germline Cx40 mutants, I75F and L229M. These Cx40 mutants impaired gap junction function via different mechanisms. I75F, substantially reduced the total number of active channels without affecting the single channel conductance. While L229M selectively impair Cx43-containing gap junction channels. Our data support the idea that mutations in the Cx40 gene may predispose the mutant carriers to AF due to an impaired gap junction function.

    4. Making Sense of Intratumor Genetic Heterogeneity: Altered Frequency of Androgen Receptor CAG Repeat Length Variants in Breast Cancer Tissues (pages 610–618)

      Bruce Gottlieb, Carlos Alvarado, Chunlin Wang, Baback Gharizadeh, Farbod Babrzadeh, Brent Richards, Gerald Batist, Mark Basik, Lenore K. Beitel and Mark Trifiro

      Article first published online: 8 MAR 2013 | DOI: 10.1002/humu.22287

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      To examine the significance of intra-tumor genetic heterogeneity in breast cancer, a novel next generation sequencing protocol was developed to measure the frequency of distribution of a variable androgen receptor gene (AR) CAG repeat length polymorphism associated with breast cancer risk. The results suggest that preferential selection of preexisting longer CAG repeat variants in breast tissues may be associated with cancer. Thus, identifying the frequency of distribution of variant genes may be essential in determining the genetic basis of oncogenesis.

    5. Heterozygous Genetic Variations of FOXP3 in Xp11.23 Elevate Breast Cancer Risk in Chinese Population via Skewed X-Chromosome Inactivation (pages 619–628)

      Jian Zheng, Jieqiong Deng, Lan Jiang, Lei Yang, Yonghe You, Min Hu, Na Li, Hongchun Wu, Wei Li, Hongbin Li, Jiachun Lu and Yifeng Zhou

      Article first published online: 8 MAR 2013 | DOI: 10.1002/humu.22284

  6. Methods

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. Nonoptical Massive Parallel DNA Sequencing of BRCA1 and BRCA2 Genes in a Diagnostic Setting (pages 629–635)

      José Luis Costa, Sónia Sousa, Ana Justino, Teresa Kay, Susana Fernandes, Luis Cirnes, Fernando Schmitt and José Carlos Machado

      Article first published online: 11 FEB 2013 | DOI: 10.1002/humu.22272

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      In this study, using the Ion Torrent PGM, we present a comprehensive MPS-Sanger sequencing based strategy for the molecular diagnosis of hereditary breast and ovarian cancer and respective analytical validation. The methodology relies on multiplex PCR amplification of the BRCA1 and BRCA2 genes combined with a dedicated variant prioritization pipeline. The workflow resulted in a strategy with a high analytical sensitivity (≥98.6%) that provides a time- and cost-effective strategy for the identification of mutations in the BRCA1 and BRCA2 genes.

    2. Genotyping by Induced Förster Resonance Energy Transfer (iFRET) Mechanism and Simultaneous Mutation Scanning (pages 636–643)

      Bartłomiej Masojć, Bohdan Górski, Thierry van de Wetering, Tadeusz Dębniak, Cezary Cybulski, Anna Jakubowska, Krzysztof Mędrek, Helena Rudnicka, Zachary Lawrence Dwight and Jan Lubiński

      Article first published online: 18 FEB 2013 | DOI: 10.1002/humu.22281

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      In this article we present a single step genotyping technique based on induced Förster Resonance Energy Transfer (iFRET) mechanism in conjunction with simultaneous mutation scanning. We show that it is a useful and cost-effective method for detection of both germline and somatic mutations.

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      DIP–STR: Highly Sensitive Markers for the Analysis of Unbalanced Genomic Mixtures (pages 644–654)

      Vincent Castella, Joëlle Gervaix and Diana Hall

      Article first published online: 5 MAR 2013 | DOI: 10.1002/humu.22280

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      Here we propose a new genetic marker, named DIP-STR that enables the analysis of DNA mixtures containing highly unbalanced proportions of DNA from two individuals. This new tool is characterized by several remarkable features: (1) capacity of detecting a minor DNA contributing less than 0.1%; (2) equal performances regardless the sex of the DNA donors; (3) high discrimination power for identity testing; finally (4) simple and low cost genotyping technique. Applications may include forensics, prenatal diagnosis and organ transplant monitoring.

  7. Letters to the Editor

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
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      Carnitine Uptake Defect (Primary Carnitine Deficiency): Risk in Genotype–Phenotype Correlation (page 655)

      Yi-Chen Chen, Yin-Hsiu Chien, Pin-Wen Chen, Nelson Leung-Sang Tang, Pao-Chin Chiu, Wuh-Liang Hwu and Ni-Chung Lee

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22286

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  8. Meeting Reports

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
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      HGV2012: Leveraging Next-Generation Technology and Large Datasets to Advance Disease Research (pages 657–660)

      Nina Gonzaludo, Hong-Xiang Zheng, Jiucun Wang, Stephen J. Chanock, Li Jin, Stephen Scherer, Cisca Wijmenga, Pui-Yan Kwok and Anthony J. Brookes

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22270

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      Getting Ready for the Human Phenome Project: The 2012 Forum of the Human Variome Project (pages 661–666)

      William S. Oetting, Peter N. Robinson, Marc S. Greenblatt, Richard G. Cotton, Tim Beck, John C. Carey, Sandra C. Doelken, Marta Girdea, Tudor Groza, Carol M. Hamilton, Ada Hamosh, Berit Kerner, Jacqueline A. L. MacArthur, Donna R. Maglott, Barend Mons, Heidi L. Rehm, Paul N. Schofield, Beverly A. Searle, Damian Smedley, Cynthia L. Smith, Inge Thomsen Bernstein, Andreas Zankl and Eric Y. Zhao

      Article first published online: 20 MAR 2013 | DOI: 10.1002/humu.22293

  9. Erratum

    1. Top of page
    2. Features
    3. Informatics
    4. Rapid Communications
    5. Brief Reports
    6. Research Articles
    7. Methods
    8. Letters to the Editor
    9. Meeting Reports
    10. Erratum
    1. You have free access to this content
      Identification of Novel Mutations Confirms PDE4D as a Major Gene Causing Acrodysostosis (page 667)

      Danielle C. Lynch, David A. Dyment, Lijia Huang, Sarah M. Nikkel, Didier Lacombe, Philippe M. Campeau, Brendan Lee, Carlos A. Bacino, Jacques L. Michaud, Francois P. Bernier, FORGE Canada Consortium, Jillian S. Parboosingh and A. Micheil Innes

      Article first published online: 11 FEB 2013 | DOI: 10.1002/humu.22290

      This article corrects:

      Identification of Novel Mutations Confirms PDE4D as a Major Gene Causing Acrodysostosis

      Vol. 34, Issue 1, 97–102, Article first published online: 9 NOV 2012

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