Human Mutation

Cover image for Vol. 35 Issue 2

February 2014

Volume 35, Issue 2

Pages i–v, 151–270

  1. Contents

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. You have free access to this content
      Contents (pages i–iii)

      Article first published online: 10 JAN 2014 | DOI: 10.1002/humu.22510

  2. In This Issue

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. You have free access to this content
  3. Reviews

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2 (pages 151–164)

      Lucia Guidugli, Aura Carreira, Sandrine M. Caputo, Asa Ehlen, Alvaro Galli, Alvaro N.A. Monteiro, Susan L. Neuhausen, Thomas V.O. Hansen, Fergus J. Couch, Maaike P.G. Vreeswijk and ; on behalf of the ENIGMA consortium

      Article first published online: 3 DEC 2013 | DOI: 10.1002/humu.22478

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      Many variants of uncertain clinical significance are identified in the BRCA2 gene, complicating the clinical management of carriers and their families. This review describes the functional assays that are currently used to establish the impact of a variant on BRCA2 protein function. In the absence of sufficient clinical and genetic data, functional assays will be a valuable and indispensable tool for the assessment of the clinical relevance of these variants.

  4. Mutation Updates

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. Insight into IKBKG/NEMO Locus: Report of New Mutations and Complex Genomic Rearrangements Leading to Incontinentia Pigmenti Disease (pages 165–177)

      Matilde Immacolata Conte, Alessandra Pescatore, Mariateresa Paciolla, Elio Esposito, Maria Giuseppina Miano, Maria Brigida Lioi, Maeve A. McAleer, Giuliana Giardino, Claudio Pignata, Alan D. Irvine, Angela E. Scheuerle, Ghislaine Royer, Smail Hadj-Rabia, Christine Bodemer, Jean-Paul Bonnefont, Arnold Munnich, Asma Smahi, Julie Steffann, Francesca Fusco and Matilde Valeria Ursini

      Article first published online: 12 DEC 2013 | DOI: 10.1002/humu.22483

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      Incontinentia pigmenti is a genomic disorder caused by mutation in IKBKG/NEMO X-linked gene. Here, we present 21 point mutations previously unreported and a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. A locus specific database, accessible at http://IKBKG.lovd.nl, will give a complete overview of all the variants identified and secure the appropriate use of genotype and phenotype information of patients.

    2. NPHS2 Mutations in Steroid-Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum (pages 178–186)

      Karim Bouchireb, Olivia Boyer, Olivier Gribouval, Fabien Nevo, Evelyne Huynh-Cong, Vincent Morinière, Raphaëlle Campait, Elisabet Ars, Damien Brackman, Jacques Dantal, Philippe Eckart, Maddalena Gigante, Beata S. Lipska, Aurélia Liutkus, André Megarbane, Nabil Mohsin, Fatih Ozaltin, Moin A. Saleem, Franz Schaefer, Kenza Soulami, Roser Torra, Nicolas Garcelon, Géraldine Mollet, Karin Dahan and Corinne Antignac

      Article first published online: 9 DEC 2013 | DOI: 10.1002/humu.22485

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      Mutations in the NPHS2 gene encoding podocin, are implicated in an autosomal recessive form of non syndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. This article reviews 25 new mutations in addition to the 101 published since the first description in 2000, as well as several variants of unknown significance and polymorphisms. Genotype–phenotype analyses establish correlations between specific variants and age at onset, ethnicity, and clinical evolution.

  5. Databases

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. Seeing the Wood for the Trees: A Minimal Reference Phylogeny for the Human Y Chromosome (pages 187–191)

      Mannis van Oven, Anneleen Van Geystelen, Manfred Kayser, Ronny Decorte and Maarten HD Larmuseau

      Article first published online: 14 NOV 2013 | DOI: 10.1002/humu.22468

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      The continuous incorporation of newly discovered mutations in the ever-expanding human Y-chromosomal phylogenetic tree strongly complicates the task of selecting suitable markers for genotyping purposes in evolutionary, genealogical, medical, and forensic studies. Therefore, we introduce a stable reference phylogeny for the Y chromosome aiming for optimal global discrimination capacity based on a minimal marker set that includes only the most resolving Y-chromosome single-nucleotide polymorphisms. Moreover, we wish to propose a common standard for Y-marker as well as Y-haplogroup nomenclature.

  6. Informatics

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. Distinct Patterns of Genetic Variations in Potential Functional Elements in Long Noncoding RNAs (pages 192–201)

      Deeksha Bhartiya, Saakshi Jalali, Sourav Ghosh and Vinod Scaria

      Article first published online: 25 NOV 2013 | DOI: 10.1002/humu.22472

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      Comprehensive analysis reveals distinct distribution of genomic variations in various long non-coding RNAs (lncRNAs). The putative functional domains in lncRNAs were found to have lower variation densities as compared to the overall length. Such regions have been analysed to look for regions of selection and disease association

    2. Variobox: Automatic Detection and Annotation of Human Genetic Variants (pages 202–207)

      Paulo Gaspar, Pedro Lopes, Jorge Oliveira, Rosário Santos, Raymond Dalgleish and José Luís Oliveira

      Article first published online: 21 NOV 2013 | DOI: 10.1002/humu.22474

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      Variobox is a new tool to support the sequence analysis workflow through the exploration of individual patient genes and their variants, taking advantage of available web-sourced knowledge. The application obtains up-to-date information about a gene and its variants, and is able to align patient sequences with reference genes and automatically infer variant annotations using HGVS nomenclature.

  7. Rapid Communications

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. You have free access to this content
      Targeted Knock-in of the Polymorphism rs61764370 Does Not Affect KRAS Expression but Reduces let-7 Levels (pages 208–214)

      Emily Hannah Crowley, Sabrina Arena, Simona Lamba, Federica Di Nicolantonio and Alberto Bardelli

      Article first published online: 27 DEC 2013 | DOI: 10.1002/humu.22487

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      We set out to understand if the cancer-associated single nucleotide polymorphism rs61764370 affects KRAS expression and downstream signalling. We generated human cell lines in which the cancer-associated polymorphism was site-specifically inserted into the exact position within the genome of the cell. Our results suggest that the polymorphism does not affect KRAS expression or downstream signalling but alters let-7 levels leading to increased proliferation of the cells

  8. Research Articles

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. Analysis of Crossover Breakpoints Yields New Insights into the Nature of the Gene Conversion Events Associated with Large NF1 Deletions Mediated by Nonallelic Homologous Recombination (pages 215–226)

      Kathrin Bengesser, Julia Vogt, Tanja Mussotter, Victor-Felix Mautner, Ludwine Messiaen, David N. Cooper and Hildegard Kehrer-Sawatzki

      Article first published online: 2 DEC 2013 | DOI: 10.1002/humu.22473

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      Nonallelic homologous recombination (NAHR) resulting in NF1-microdeletions was found to be associated with continuous gene conversion mediated by long-patch mismatch-repair in 51 deletions investigated. The continuous gene conversion patterns observed are responsible for very precise transitions of the recombining paralogs at the deletion junctions. However, one NF1-microdeletion of postzygotic origin was processed without mismatch-repair, causing post-mitotic segregation (PMS) of different recombination products. Hence, PMS may be responsible both for breakpoint location heterogeneity and somatic mosaicism of NAHR-mediated genomic rearrangements.

    2. Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway (pages 227–235)

      Laia Paré-Brunet, Dylan Glubb, Patrick Evans, Antoni Berenguer-Llergo, Amy S. Etheridge, Andrew D. Skol, Anna Di Rienzo, Shiwei Duan, Eric R. Gamazon and Federico Innocenti

      Article first published online: 27 NOV 2013 | DOI: 10.1002/humu.22475

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      Listed genes (highlighted in red) selected for resequencing in the VEGF pathway (www.pharmgkb.org): CRK, FLT1, FRS2, GRB2, NRP1, PGF, RAF1, VEGFA and VEGFB. In some genes one or more genes are involved, RAS refers to KRAS, NRAS. PRKC refers to PRKCA and PRKCE. PIK3 refers to PIK3C2A, PIK3C2B and PIK3R5. MAP2K refers to MAP2K6. MAPK refers to MAPK1, MAPK11, MAPK14, and MAPK3. AKT refers to AKT1. Integrin refers to ITGAV and ITGB5

    3. MYH9-Related Disease: A Novel Prognostic Model to Predict the Clinical Evolution of the Disease Based on Genotype–Phenotype Correlations (pages 236–247)

      Alessandro Pecci, Catherine Klersy, Paolo Gresele, Kieran J.D. Lee, Daniela De Rocco, Valeria Bozzi, Giovanna Russo, Paula G. Heller, Giuseppe Loffredo, Matthias Ballmaier, Fabrizio Fabris, Eloise Beggiato, Walter H.A. Kahr, Nuria Pujol-Moix, Helen Platokouki, Christel Van Geet, Patrizia Noris, Preethi Yerram, Cedric Hermans, Bernhard Gerber, Marina Economou, Marco De Groot, Barbara Zieger, Erica De Candia, Vincenzo Fraticelli, Rogier Kersseboom, Giorgina B. Piccoli, Stefanie Zimmermann, Tiziana Fierro, Ana C. Glembotsky, Fabrizio Vianello, Carlo Zaninetti, Elena Nicchia, Christiane Güthner, Carlo Baronci, Marco Seri, Peter J. Knight, Carlo L. Balduini and Anna Savoia

      Article first published online: 12 DEC 2013 | DOI: 10.1002/humu.22476

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      MYH9-related disease (MYH9-RD), the complex syndromic disorder deriving from mutations in MYH9, is characterized by a considerable variability in clinical evolution. This paper identifies significant genotype–phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far. These data allow us to predict the evolution of the disease associated to genotypes responsible for 85% of MYH9-RD cases, providing an essential tool for patients' clinical management and genetic counseling and suggesting new mechanisms for molecular pathogenesis of the disease.

    4. You have full text access to this OnlineOpen article
      A 129-kb Deletion on Chromosome 12 Confers Substantial Protection Against Rheumatoid Arthritis, Implicating the Gene SLC2A3 (pages 248–256)

      Colin D. Veal, Katherine E. Reekie, Johnny C. Lorentzen, Peter K. Gregersen, Leonid Padyukov and Anthony J. Brookes

      Article first published online: 2 DEC 2013 | DOI: 10.1002/humu.22471

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      We describe a copy number variant for which deletion alleles confer a protective affect against Rheumatoid Arthritis. Genotyping in Swedish samples (2403 cases, 1269 controls) revealed a significantly lower frequency of deletion variants in RA cases (p = 0.0012). A similar reduction was seen in UK and US samples, combining the three datasets produces a Mantel–Haenszel OR of 0.497 (p < 0.0002). The deletion spans SLC2A3, a high affinity glucose transporter important in the immune response and chondrocyte metabolism, key aspects of RA pathogenesis

    5. The ZZ Domain of Dystrophin in DMD: Making Sense of Missense Mutations (pages 257–264)

      Adeline Vulin, Nicolas Wein, Dana M. Strandjord, Eric K. Johnson, Andrew R. Findlay, Baijayanta Maiti, Michael T. Howard, Yuuki J. Kaminoh, Laura E. Taylor, Tabatha R. Simmons, Will C. Ray, Federica Montanaro, Jim M. Ervasti and Kevin M. Flanigan

      Article first published online: 2 DEC 2013 | DOI: 10.1002/humu.22479

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      Missense mutations in the dystrophin ZZ domain result in Duchenne muscular dystrophy. In vivo studies of two mutations of zinc-finger defining cysteine residues (p.Cys3313Tyr and p.Cys3340Tyr) and one non-cysteine mutation (p.Asp3335His) demonstrate no β-dystroglycan binding of any, but this is due to two different mechanisms. The cysteine mutations result in unstable proteins that are rapidly degraded, whereas the aspartic acid mutation interferes with β-dystroglycan binding despite normal localization to the sarcolemmal membrane, possibly mediated by preserved a-syntrophin binding (co-immunoprecipitation, right).

  9. Meeting Reports

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. You have free access to this content
  10. Erratum

    1. Top of page
    2. Contents
    3. In This Issue
    4. Reviews
    5. Mutation Updates
    6. Databases
    7. Informatics
    8. Rapid Communications
    9. Research Articles
    10. Meeting Reports
    11. Erratum
    1. You have free access to this content
      A Short-Read Multiplex Sequencing Method for Reliable, Cost-Effective and High-Throughput Genotyping in Large-Scale Studies (page 270)

      Hongzhi Cao, Yu Wang, Wei Zhang, Xianghua Chai, Xiandong Zhang, Shiping Chen, Fan Yang, Caifen Zhang, Yulai Guo, Ying Liu, Zhoubiao Tang, Caifen Chen, Yaxin Xue, Hefu Zhen, Yinyin Xu, Bin Rao, Tao Liu, Meiru Zhao, Wenwei Zhang, Yingrui Li, Xiuqing Zhang, Laurent C. A. M. Tellier, Anders Krogh, Karsten Kristiansen, Jun Wang and Jian Li

      Article first published online: 19 DEC 2013 | DOI: 10.1002/humu.22486

      This article corrects:

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