Human Mutation

Cover image for Vol. 35 Issue 3

March 2014

Volume 35, Issue 3

Pages i–v, 271–394

  1. Contents

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. You have free access to this content
      Contents (pages i–iii)

      Version of Record online: 13 FEB 2014 | DOI: 10.1002/humu.22512

  2. In This Issue

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. You have free access to this content
      Disease-causing Enhancer Variants: A Question of Penetrance (page v)

      Sergio Ottolenghi

      Version of Record online: 13 FEB 2014 | DOI: 10.1002/humu.22406

  3. Informatics

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. ICO Amplicon NGS Data Analysis: A Web Tool for Variant Detection in Common High-Risk Hereditary Cancer Genes Analyzed by Amplicon GS Junior Next-Generation Sequencing (pages 271–277)

      Adriana Lopez-Doriga, Lídia Feliubadaló, Mireia Menéndez, Sergio Lopez-Doriga, Francisco D. Morón-Duran, Jesús del Valle, Eva Tornero, Eva Montes, Raquel Cuesta, Olga Campos, Carolina Gómez, Marta Pineda, Sara González, Victor Moreno, Gabriel Capellá and Conxi Lázaro

      Version of Record online: 6 DEC 2013 | DOI: 10.1002/humu.22484

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      We present a free, accurate and user-friendly web-based tool to perform the bioinformatic analysis of data obtained using the GS Junior sequencer for mutational analysis of high-risk cancer susceptibility genes. Our algorithm detects and filters sequence variants, providing coverage information and allowing the user to customize some of the basic parameters. The identified variants are classified according to our ICO Mutation Database. The software described in the manuscript is available at http://bioinfo.iconcologia.net/aplicNGS.

    2. Heterozygote PCR Product Melting Curve Prediction (pages 278–282)

      Zachary L. Dwight, Robert Palais, Jana Kent and Carl T. Wittwer

      Version of Record online: 3 JAN 2014 | DOI: 10.1002/humu.22494

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      uMelt Hets is a freely available, web application for use in predicting and investigating heterozygote products commonly found in melting curve analysis applications. This software provides valuable insight for efficient genotyping design and quality control of melting curve experiments. Experimental results indicate that the type of single nucleotide variant can alter the contribution of heteroduplex products as well as the effect of ions on mismatched bases, changing the shape of the heterozygote composite melt curve

  4. Rapid Communications

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. You have full text access to this OnlineOpen article
      DIAMUND: Direct Comparison of Genomes to Detect Mutations (pages 283–288)

      Steven L. Salzberg, Mihaela Pertea, Jill A. Fahrner and Nara Sobreira

      Version of Record online: 13 FEB 2014 | DOI: 10.1002/humu.22503

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      DIAMUND is an accurate, efficient computational method for directly comparing DNA sequences to search for de novo mutations. It is designed for comparing family members or multiple tissues from the same individual.

  5. Brief Reports

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. You have full text access to this OnlineOpen article
      A Homozygous Mutation in the TUB Gene Associated with Retinal Dystrophy and Obesity (pages 289–293)

      Arundhati Dev Borman, Laura R. Pearce, Donna S. Mackay, Kerstin Nagel-Wolfrum, Alice E. Davidson, Robert Henderson, Sumedha Garg, Naushin H. Waseem, Andrew R. Webster, Vincent Plagnol, Uwe Wolfrum, I. Sadaf Farooqi and Anthony T. Moore

      Version of Record online: 20 DEC 2013 | DOI: 10.1002/humu.22482

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      We report the first homozygous mutation in TUB associated with retinal dystrophy and obesity.

    2. You have full text access to this OnlineOpen article
      Germline Mutations of Inhibins in Early-Onset Ovarian Epithelial Tumors (pages 294–297)

      Isabelle Tournier, Régine Marlin, Kelly Walton, Françoise Charbonnier, Sophie Coutant, Jean-Christophe Théry, Camille Charbonnier, Cailyn Spurrell, Myriam Vezain, Lorena Ippolito, Gaëlle Bougeard, Horace Roman, Julie Tinat, Jean-Christophe Sabourin, Dominique Stoppa-Lyonnet, Olivier Caron, Brigitte Bressac-de Paillerets, Dominique Vaur, Mary-Claire King, Craig Harrison and Thierry Frebourg

      Version of Record online: 27 DEC 2013 | DOI: 10.1002/humu.22489

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      Using the trio exome sequencing strategy, we identified a germline de novo mutation of the INHBA gene in a patient who developed sporadic bilateral ovarian epithelial adenocarcinomas at 21 years of age and showed that this mutation affects the inhibin/activin ratio. Identification in patients with early-onset ovarian tumors of other variations affecting this gene or its partner INHA, functional assays and statistical tests indicate that germline alterations of the inhibin/activin pathway may contribute to the genetic determinism of early-onset epithelial ovarian tumors.

    3. Novel Dynein DYNC1H1 Neck and Motor Domain Mutations Link Distal Spinal Muscular Atrophy and Abnormal Cortical Development (pages 298–302)

      Chiara Fiorillo, Francesca Moro, Julie Yi, Sarah Weil, Giacomo Brisca, Guja Astrea, Mariasavina Severino, Alessandro Romano, Roberta Battini, Andrea Rossi, Carlo Minetti, Claudio Bruno, Filippo M. Santorelli and Richard Vallee

      Version of Record online: 3 JAN 2014 | DOI: 10.1002/humu.22491

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      In this work we delineate the clinical and molecular features of two novel mutations in the tail and motor domains of cytoplasmic dynein (DYNC1H1) and provide evidence for the importance of both regions in normal physiological function by demonstrating a deleterious effect on the organization of the Golgi apparatus in patient fibroblasts.

      In addition we describe a dual clinical picture which embraces a defect of spinal nerves with brain malformation, proposing a continuum of phenotype associated to dynein defect in human.

    4. An Impairment of Long Distance SOX10 Regulatory Elements Underlies Isolated Hirschsprung Disease (pages 303–307)

      Laure Lecerf, Anthula Kavo, Macarena Ruiz-Ferrer, Viviane Baral, Yuli Watanabe, Asma Chaoui, Veronique Pingault, Salud Borrego and Nadege Bondurand

      Version of Record online: 8 JAN 2014 | DOI: 10.1002/humu.22499

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      Screening of 144 isolated Hirschsprung disease patients led to the identification of one deletion and two point mutations altering SOX10 enhancers. In contrast to the deletion, both variations are inherited from the healthy fathers. Interestingly, both patients are also heterozygous for a common RET polymorphism inherited from their respective mothers, which could act as an additional genetic risk factor. In vitro functional analysis revealed one of the variation disrupts SOX10 autoregulation, whereas the other affects AP2a and SOX10 synergistic activity.

  6. Research Articles

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. Retinitis Pigmentosa Mutations of SNRNP200 Enhance Cryptic Splice-Site Recognition (pages 308–317)

      Zuzana Cvačková, Daniel Matějů and David Staněk

      Version of Record online: 2 DEC 2013 | DOI: 10.1002/humu.22481

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      BRR2 is an essential component of the spliceosomal U5 snRNP. (A) We showed that depletion of BRR2 enhances 5 cryptic splice site utilization of -lglobin reporter. (B) Neither of the tested retinitis pigmentosa mutations of BRR2 (BRR2-RP) affected BRR2 integration into the U5 snRNP or the spliceosome but both mutations weakened the BRR2 proofreading activity

    2. Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues (pages 318–328)

      Miguel A. Molina-Vila, Nuria Nabau-Moretó, Cristian Tornador, Amit J. Sabnis, Rafael Rosell, Xavier Estivill, Trever G. Bivona and Cristina Marino-Buslje

      Version of Record online: 8 JAN 2014 | DOI: 10.1002/humu.22493

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      Activating mutations of protein kinases play a key role in tumorogenesis and are targets for new generations of drugs. We performed the first analysis of the 407 activating mutations described in the literature, with affect 41 protein kinases. Activating mutations do not associate with conserved or catalytic residues but cluster around three segments that act as “brakes” of the kinase activity (HS1–HS3). Therefore, bioinformatics methods based on conservation can not be used to predict activating mutations and new tools are needed.

    3. Tumor Heterogeneity Revealed by KRAS, BRAF, and PIK3CA Pyrosequencing: KRAS and PIK3CA Intratumor Mutation Profile Differences and Their Therapeutic Implications (pages 329–340)

      Vivian Kosmidou, Eftychia Oikonomou, Margarita Vlassi, Spyros Avlonitis, Anastasia Katseli, Iraklis Tsipras, Despina Mourtzoukou, Georgios Kontogeorgos, Georgios Zografos and Alexander Pintzas

      Version of Record online: 15 JAN 2014 | DOI: 10.1002/humu.22496

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      Remarkable tumor heterogeneity is revealed by different KRAS mutations in the tumor center versus the periphery of several colorectal cancer specimens. Overall, 44% of the examined samples presented different KRAS mutations between the tumor center and the tumor periphery. In addition, 34.8% of the samples analyzed showed differences in KRAS mutational status between two different portions of the same tumor center

    4. Gender and Cell-Type-Specific Effects of the Transcription-Coupled Repair Protein, ERCC6/CSB, on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders (pages 341–349)

      Xiao-Nan Zhao and Karen Usdin

      Version of Record online: 13 JAN 2014 | DOI: 10.1002/humu.22495

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      The Fragile X-related disorders (FXDs) result from expansion of a CGG/CCG-repeat tract in the 5' UTR of the FMR1 gene. The expansion mechanism is unknown but there is evidence to suggest that Transcription Coupled Repair (TCR) might be involved. We show here in a mouse model of the FXDs, that the loss of CSB, a protein essential for TCR, only affects the number of expanded alleles transmitted by older females. These data have a number of implications for the mechanism of expansion in the FXDs.

    5. Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality (pages 350–355)

      Stefanie Belet, Nathalie Fieremans, Xuan Yuan, Hilde Van Esch, Jelle Verbeeck, Zhaohui Ye, Linzhao Cheng, Brett R. Brodsky, Hao Hu, Vera M. Kalscheuer, Robert A. Brodsky and Guy Froyen

      Version of Record online: 13 JAN 2014 | DOI: 10.1002/humu.22498

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      Loss-of-function mutations in the PIGA gene are normally lethal in utero. In this study however, we report a loss-of-function PIGA mutation in boys from a large family who were diagnosed with a severe form of intellectual disability. Based on functional assays, we provide evidence that this mutation results in the production of a shorter PIGA protein with residual functionality which is sufficient to rescue the lethality but still results in clinical features including intellectual disability.

    6. Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin-1A (pages 356–367)

      Maria Virginia Soldovieri, Nadia Boutry-Kryza, Mathieu Milh, Diane Doummar, Benedicte Heron, Emilie Bourel, Paolo Ambrosino, Francesco Miceli, Michela De Maria, Nathalie Dorison, Stephane Auvin, Bernard Echenne, Julie Oertel, Audrey Riquet, Laetitia Lambert, Marion Gerard, Anne Roubergue, Alain Calender, Cyril Mignot, Maurizio Taglialatela and Gaetan Lesca

      Version of Record online: 13 JAN 2014 | DOI: 10.1002/humu.22500

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      Mutations in KCNQ2 and KCNQ3, encoding for Kv7.2 and KV7.3 voltage-dependent K+ channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity.

      We describe data from 17 patients/families with the diagnosis of benign familial neonatal epilepsy and with a mutation in KCNQ2 (n = 16) or KCNQ3 (n = 1). Electrophysiological studies in mammalian cells revealed that newly found substitutions displayed reduced current densities. In addition, some mutations impair channel regulation by syntaxin-1-A, highlighting a novel pathogenic mechanism for KCNQ2-related epilepsies.

    7. Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB) (pages 368–376)

      Raffaella De Pace, Maria Francisca Coutinho, Friedrich Koch-Nolte, Friedrich Haag, Maria João Prata, Sandra Alves, Thomas Braulke and Sandra Pohl

      Version of Record online: 15 JAN 2014 | DOI: 10.1002/humu.22502

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      The lysosomal disorder mucolipidosis II (MLII) is caused by mutations in GNPTAB encoding an α/β-subunit precursor protein of the oligomeric Golgi-resident GlcNAc-1-phosphotransferase. This enzyme forms mannose 6-phosphate targeting signals on lysosomal enzymes prerequisite for lysosomal function. Here, we analyzed the expression of six missense and frameshift mutations identified in patients and found that they either affect ER-Golgi transport, site-1 protease mediated proteolytic activation or mRNA stability of the α/β-subunit precursor protein, and associate with different clinical courses of the disease

    8. Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains (pages 377–383)

      Lieselot Vanmarsenille, Maila Giannandrea, Nathalie Fieremans, Jelle Verbeeck, Stefanie Belet, Martine Raynaud, Annick Vogels, Katrin Männik, Katrin Õunap, Vigneron Jacqueline, Sylvain Briault, Hilde Van Esch, Patrizia D'Adamo and Guy Froyen

      Version of Record online: 13 JAN 2014 | DOI: 10.1002/humu.22497

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      In this study, we identified the same duplication of 500 kb on the X chromosome in unrelated male patients with intellectual disability. From the different genes included, the RAB39B gene was our prime candidate because loss-of-function had been described in relation to this condition. Indeed, overexpression of this gene in primary neuronal cells resulted in a decrease of neuronal branching and presynaptic terminals, providing evidence that an increased dosage of RAB39B in humans can affect neuronal development and function.

  7. Methods

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. Enhanced Sensitivity for Detection of Low-Level Germline Mosaic RB1 Mutations in Sporadic Retinoblastoma Cases Using Deep Semiconductor Sequencing (pages 384–391)

      Zhao Chen, Kimberly Moran, Jennifer Richards-Yutz, Erik Toorens, Daniel Gerhart, Tapan Ganguly, Carol L. Shields and Arupa Ganguly

      Version of Record online: 20 DEC 2013 | DOI: 10.1002/humu.22488

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      Enhanced Sensitivity of Mosaic Mutation Detection in lymphocyte DNA of Bilateral Retinoblastoma using Deep sequencing: comparision with Sanger sequencing and Taqman Assays.

  8. Letter to the Editor

    1. Top of page
    2. Contents
    3. In This Issue
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Letter to the Editor
    1. You have free access to this content

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