Human Mutation

Cover image for Human Mutation

October 2013

Volume 34, Issue 10

Pages v–v, 1313–1448

  1. Features

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. You have free access to this content
    2. You have free access to this content
  2. Special Articles

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. You have free access to this content
      Best Practice Guidelines for the Use of Next-Generation Sequencing Applications in Genome Diagnostics: A National Collaborative Study of Dutch Genome Diagnostic Laboratories (pages 1313–1321)

      Marjan M. Weiss, Bert Van der Zwaag, Jan D. H. Jongbloed, Maartje J. Vogel, Hennie T. Brüggenwirth, Ronald H. Lekanne Deprez, Olaf Mook, Claudia A. L. Ruivenkamp, Marjon A. van Slegtenhorst, Arthur van den Wijngaard, Quinten Waisfisz, Marcel R. Nelen and Nienke van der Stoep

      Version of Record online: 19 AUG 2013 | DOI: 10.1002/humu.22368

    2. You have full text access to this OnlineOpen article
      Reflecting on Earlier Experiences with Unsolicited Findings: Points to Consider for Next-Generation Sequencing and Informed Consent in Diagnostics (pages 1322–1328)

      Tessel Rigter, Lidewij Henneman, Ulf Kristoffersson, Alison Hall, Helger G. Yntema, Pascal Borry, Holger Tönnies, Quinten Waisfisz, Mariet W. Elting, Wybo J. Dondorp and Martina C. Cornel

      Version of Record online: 16 JUL 2013 | DOI: 10.1002/humu.22370

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      High-throughput nucleotide sequencing is increasingly being used in clinical diagnostics. The increased chance of detecting unsolicited findings requires decisions on disclosure of these findings and poses a challenge for the informed consent procedure. This article discusses the ethical and practical dilemmas encountered when contemplating informed consent for next generation sequencing in diagnostics from a multidisciplinary point of view. We hereby aim to provide a sound basis for developing guidelines for optimizing the informed consent procedure

  3. Mutation Updates

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. IL-12Rβ1 Deficiency: Mutation Update and Description of the IL12RB1 Variation Database (pages 1329–1339)

      Esther van de Vosse, Margje H. Haverkamp, Noe Ramirez-Alejo, Mónica Martinez-Gallo, Lizbeth Blancas-Galicia, Ayşe Metin, Ben Zion Garty, Çağman Sun-Tan, Arnon Broides, Roelof A. de Paus, Özlem Keskin, Deniz Çağdaş, Ilhan Tezcan, Encarna Lopez-Ruzafa, Juan I. Aróstegui, Jacov Levy, Francisco J. Espinosa-Rosales, Özden Sanal, Leopoldo Santos-Argumedo, Jean-Laurent Casanova, Stephanie Boisson-Dupuis, Jaap T. van Dissel and Jacinta Bustamante

      Version of Record online: 8 AUG 2013 | DOI: 10.1002/humu.22380

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      IL-12Rβ1 deficiency is an autosomal recessive disorder that predisposes to severe infections with otherwise poorly pathogenic mycobacteria and salmonella. Seventy unique IL12RB1 mutations in 198 individuals are known that almost invariably result in the same cellular phenotype: absence of IL-12Rβ1 expression on the cell surface (in all but one) and absence of IL-12 and IL-23 responses (in all). No genotype–phenotype relationship exists. This manuscript reviews the function of IL-12Rβ1 and molecular genetics of IL12RB1, and introduces the IL12RB1 mutation database.

  4. Informatics

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. CPAP: Cancer Panel Analysis Pipeline (pages 1340–1346)

      Po-Jung Huang, Yuan-Ming Yeh, Ruei-Chi Gan, Chi-Ching Lee, Ting-Wen Chen, Cheng-Yang Lee, Hsuan Liu, Shu-Jen Chen and Petrus Tang

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22386

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      CPAP is a web-based automatic pipeline to annotate and visualize genomic variants found in cancer panel sequencing. CPAP not only integrates various data sources such as dbSNP, the 1000 Genomes Project, and COSMIC, but also provides the prediction of the functional impact of variants as generated by popular prediction tools (e.g., PolyPhen, SIFT, and MutationTaster). The generated results can be viewed either in the Circos view with pop-up annotations or in the Table view, where results are filterable.

  5. Brief Reports

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. You have full text access to this OnlineOpen article
      HOXA2 Haploinsufficiency in Dominant Bilateral Microtia and Hearing Loss (pages 1347–1351)

      Kerry K. Brown, Lucas M. Viana, Cecilia C. Helwig, Maria A. Artunduaga, Lourdes Quintanilla-Dieck, Patricia Jarrin, Gabriel Osorno, Barbara McDonough, Steven R. DePalma, Roland D. Eavey, Jonathan G. Seidman and Christine E. Seidman

      Version of Record online: 11 JUL 2013 | DOI: 10.1002/humu.22367

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      Whole exome sequencing defines a rare nonsense mutation in HOXA2 that causes autosomal dominant nonsyndromic microtia and hearing loss.

    2. Founder Mutation in RSPH4A Identified in Patients of Hispanic Descent with Primary Ciliary Dyskinesia (pages 1352–1356)

      M. Leigh Anne Daniels, Margaret W. Leigh, Stephanie D. Davis, Michael C. Armstrong, Johnny L. Carson, Milan Hazucha, Sharon D. Dell, Maria Eriksson, Francis S. Collins, Michael R. Knowles and Maimoona A. Zariwala

      Version of Record online: 6 AUG 2013 | DOI: 10.1002/humu.22371

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      Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic otosino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine Hispanic subjects with Puerto Rican ancestry with PCD. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent.

    3. Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12 (pages 1357–1360)

      Guida Landouré, Peng-Peng Zhu, Charles M. Lourenço, Janel O. Johnson, Camilo Toro, Katherine V. Bricceno, Carlo Rinaldi, Katherine G. Meilleur, Modibo Sangaré, Oumarou Diallo, Tyler M. Pierson, Hiroyuki Ishiura, Shoji Tsuji, Nichole Hein, John K. Fink, Marion Stoll, Garth Nicholson, Michael A. Gonzalez, Fiorella Speziani, Alexandra Dürr, Giovanni Stevanin, Leslie G. Biesecker, for the NIH Intramural Sequencing Center, John Accardi, Dennis M. D. Landis, William A. Gahl, Bryan J. Traynor, Wilson Marques Jr, Stephan Züchner, Craig Blackstone, Kenneth H. Fischbeck and Barrington G. Burnett

      Version of Record online: 12 AUG 2013 | DOI: 10.1002/humu.22378

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      We report a Malian and Brazilian families affected with hereditary spastic paraplegia (SPG43) and “forme frustre” neurodegeneration with brain iron accumulation (NBIA), respectively. The same mutation (C19orf12, p.Ala63Pro) and haplotype were found in these families, but MRI scans showed no brain iron deposition in the Malian subjects. Heterologous expression of this SPG43 and NBIA variant resulted in alteration in the subcellular distribution of C19orf12. Further studies are needed to unravel other genetic or environmental factors underlining these phenotypic differences.

    4. β-Thalassemia Due to Intronic LINE-1 Insertion in the β-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the β-GlobinL1 Allele (pages 1361–1365)

      Lucie Lanikova, Jana Kucerova, Karel Indrak, Martina Divoka, Jean-Pierre Issa, Thalia Papayannopoulou, Josef T. Prchal and Vladimir Divoky

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22383

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      β-thalassemia is a common inherited hemoglobin disorder characterized by quantitative reduction of functional β-globin chains. Here we report a novel molecular etiology for β+-thalassemia caused by the insertion of a LINE-1 element into the intron-2 of the β-globin gene. Reduction in steady-state level of β-globin mRNA is caused by a combination of several molecular mechanisms: decreased production of full-length β-globinL1 primary transcript, unstable abnormally spliced β-globin mRNAs, and epigenetic transcriptional repression of β-globinL1 allele involving DNA hypermethylation and histone deacetylation.

    5. Novel Mutations in SCO1 as a Cause of Fatal Infantile Encephalopathy and Lactic Acidosis (pages 1366–1370)

      Scot C. Leary, Hana Antonicka, Florin Sasarman, Woranontee Weraarpachai, Paul A. Cobine, Min Pan, Garry K. Brown, Ruth Brown, Jacek Majewski, Kevin C. H. Ha, Shamima Rahman and Eric A. Shoubridge

      Version of Record online: 12 AUG 2013 | DOI: 10.1002/humu.22385

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      SCO1 is a mitochondrial metallochaperone with essential functions in cytochrome c oxidase assembly and the regulation of cellular copper homeostasis. Mutations in SCO1 are exceedingly rare, and only two pedigrees had been identified before this study. Unlike earlier pedigrees, which expressed distinct allelic variants of SCO1 (P174L, G132S), the patient we describe here harbored a novel M294V missense mutation and presented with a fatal encephalopathy, the third unique clinical course of disease associated with SCO1 mutations

  6. Research Articles

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. Structure-Function Analysis of the Human Ferroportin Iron Exporter (SLC40A1): Effect of Hemochromatosis Type 4 Disease Mutations and Identification of Critical Residues (pages 1371–1380)

      Gérald Le Gac, Chandran Ka, Rozenn Joubrel, Isabelle Gourlaouen, Pierre Lehn, Jean-Paul Mornon, Claude Férec and Isabelle Callebaut

      Version of Record online: 10 SEP 2013 | DOI: 10.1002/humu.22369

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      Ribbon representation of the model of the human ferroportin 3D structure. The structure is organized into two equivalent domains, each possessing six helices. Ribbons are rainbow colored (from blue to red) in the two halves to highlight the duplication and the equivalent helices. The solvent-accessible surface of residues participating in the pore is presented in yellow.

    2. Clinical and Radiographic Features of the Autosomal Recessive form of Brachyolmia Caused by PAPSS2 Mutations (pages 1381–1386)

      Aritoshi Iida, Pelin Özlem Simsek-Kiper, Shuji Mizumoto, Touma Hoshino, Nursel Elcioglu, Eva Horemuzova, Stefan Geiberger, Gozde Yesil, Hülya Kayserili, Gülen Eda Utine, Koray Boduroglu, Shigehiko Watanabe, Hirofumi Ohashi, Yasemin Alanay, Kazuyuki Sugahara, Gen Nishimura and Shiro Ikegawa

      Version of Record online: 26 JUL 2013 | DOI: 10.1002/humu.22377

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      Brachyolmia is a heterogeneous group of skeletal dysplasia characterized by generalized platyspondyly without significant long-bone abnormalities. We revealed previously that an autosomal recessive form of brachyolmia is caused by mutations of PAPSS2 that encodes PAPS (3′-phosphoadenosine 5′-phosphosulfate) synthase 2. In this study, we identified nine types of mutations in 13 patients with brachyolmia from unrelated 10 families and characterized clinical and radiographic features of the PAPSS2-brachyolmia. Enzyme assays for missense mutations confirmed that PAPSS2-brachyolmia is caused by PAPSS2 deficiency.

    3. In Vitro Correction of a Pseudoexon-Generating Deep Intronic Mutation in LGMD2A by Antisense Oligonucleotides and Modified Small Nuclear RNAs (pages 1387–1395)

      Lorea Blázquez, Ana Aiastui, Maria Goicoechea, Mafalda Martins de Araujo, Aurélie Avril, Cyriaque Beley, Luis García, Juan Valcárcel, Puri Fortes and Adolfo López de Munain

      Version of Record online: 7 AUG 2013 | DOI: 10.1002/humu.22379

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      c.1782+1072G>C mutation is the first deep-intronic mutation in the CAPN3 gene, which leads to LGMD2A. The mutation causes the inclusion of a pseudoexon in mature CAPN3 mRNA. In this work, we demonstrate mutation pathogenicity with a minigene assay and we induce splicing modulation with Antisense Oligonucleotides (AONs) and modified U-snRNAs. In addition, AON treatment restores correct splicing in fibroblasts from a LGMD2A patient which harbors this mutation. Our results indicate that SRSF1 splicing factor is involved in pseudoexon activation.

    4. Characterization of Variants in the Glucosylceramide Synthase Gene and their Association with Type 1 Gaucher Disease Severity (pages 1396–1403)

      Pilar Alfonso, Joaquín Navascués, Silvia Navarro, Pilar Medina, Alfonso Bolado-Carrancio, Vanesa Andreu, Pilar Irún, José Carlos Rodríguez-Rey, Miguel Pocoví, Francisco España and Pilar Giraldo

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22381

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      We examined glucosylceramide synthase gene (UGCG) polymorphisms and their correlation with Gaucher disease (GD) severity to explain the variability. Heterozygous [N370S]+[L444P] patients with c.[-232_-241ins10 (+) 98++++50G] haplotype had a significantly lower disease severity scoring system (DS3) score in relation to patients carrying only one of these polymorphisms. Luciferase reporter assays showed that [c.-232_-241ins10;98+50A], [c.-232nonins;98+50G] and [c.-232_-241ins10;98+50G] haplotypes significantly reduced promoter activity. In conclusion, the c.-232_-241ins10 and c.98+50A>G variants are modifying factors of GD severity.

    5. Characterization of SLC26A9 in Patients with CF-Like Lung Disease (pages 1404–1414)

      Naziha Bakouh, Thierry Bienvenu, Annick Thomas, Jordi Ehrenfeld, Huguette Liote, Delphine Roussel, Philippe Duquesnoy, Nicolette Farman, Marion Viel, Baya Cherif-Zahar, Serge Amselem, Rola Abou Taam, Aleksander Edelman, Gabrielle Planelles and Isabelle Sermet-Gaudelus

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22382

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      We report the functional characterization of 2 mutations in SLC26A9 evidenced in patients presenting with idiopathic bronchiectasis. p.Arg575Trp and p.Val486Ile decrease SLC26A9-mediated chloride (Cl-) current in Xenopus laevis oocytes. Additionally, p.Arg575Trp also prevents SLC26A9-mediated CFTR activation (see CFTR-mediated currents in Xenopus Laevis oocytes expressing either CFTR alone or CFTR and SLC26A9-WT or SLC26A9-p.Arg575Trp). Further structure-function analysis led us to propose a site on the SLC26A9-STAS domain for the CFTR-SLC26A9 interaction. Such mutations may trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl- transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.

    6. Recurrent HERV-H-Mediated 3q13.2–q13.31 Deletions Cause a Syndrome of Hypotonia and Motor, Language, and Cognitive Delays (pages 1415–1423)

      Andrey Shuvarikov, Ian M. Campbell, Piotr Dittwald, Nicholas J. Neill, Martin G. Bialer, Christine Moore, Patricia G. Wheeler, Stephanie E. Wallace, Mark C. Hannibal, Michael F. Murray, Monica A. Giovanni, Deborah Terespolsky, Sandi Sodhi, Matteo Cassina, David Viskochil, Billur Moghaddam, Kristin Herman, Chester W. Brown, Christine R. Beck, Anna Gambin, Sau Wai Cheung, Ankita Patel, Allen N. Lamb, Lisa G. Shaffer, Jay W. Ellison, J. Britt Ravnan, Paweł Stankiewicz and Jill A. Rosenfeld

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22384

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      A recurrent microdeletion of 3q13.2q13.31 results in a syndrome of hypotonia, language and motor delays, and variable dysmorphisms, cognitive delays, and behavior problems. The deletions likely arise via non-allelic homologous recombination (NAHR) between flanking retroviral elements, which contain shorter segments of homology than observed with repetitive sequences leading to more canonical NAHR events.

    7. Evaluation of a 5-Tier Scheme Proposed for Classification of Sequence Variants Using Bioinformatic and Splicing Assay Data: Inter-Reviewer Variability and Promotion of Minimum Reporting Guidelines (pages 1424–1431)

      Logan C. Walker, Phillip J. Whiley, Claude Houdayer, Thomas V. O. Hansen, Ana Vega, Marta Santamarina, Ana Blanco, Laura Fachal, Melissa C. Southey, Alan Lafferty, Mara Colombo, Giovanna De Vecchi, Paolo Radice, Amanda B. Spurdle and on behalf of the ENIGMA consortium

      Version of Record online: 13 AUG 2013 | DOI: 10.1002/humu.22388

  7. Methods

    1. Top of page
    2. Features
    3. Special Articles
    4. Mutation Updates
    5. Informatics
    6. Brief Reports
    7. Research Articles
    8. Methods
    1. Accurately Identifying Low-Allelic Fraction Variants in Single Samples with Next-Generation Sequencing: Applications in Tumor Subclone Resolution (pages 1432–1438)

      Lucy F. Stead, Kate M. Sutton, Graham R. Taylor, Philip Quirke and Pamela Rabbitts

      Version of Record online: 11 JUL 2013 | DOI: 10.1002/humu.22365

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      Cancers evolve, resulting in polyclonal tumours containing related, but genetically distinct, subclones. Somatic mutations that are distinct to small subclones will have a low variant frequency when DNA is extracted, and sequenced, from the tumour en masse. We have found that, overall, VarScan2 most accurately a) detects these low-allelic fraction variants and b) assigns their true allelic frequency. A sequencing depth of at least 250x is required to identify variants that have as few as 5% variant alleles.

    2. Detection of Clinically Relevant Copy Number Variants with Whole-Exome Sequencing (pages 1439–1448)

      Joep de Ligt, Philip M. Boone, Rolph Pfundt, Lisenka E.L.M. Vissers, Todd Richmond, Joel Geoghegan, Kathleen O'Moore, Nicole de Leeuw, Christine Shaw, Han G. Brunner, James R. Lupski, Joris A. Veltman and Jayne Y. Hehir-Kwa

      Version of Record online: 30 AUG 2013 | DOI: 10.1002/humu.22387

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      Copy number variation (CNV) is a common source of genetic variation implicated in many genomic disorders. We evaluate the utility of WES to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Of the 12 clinically relevant CNVs 11 were detected via read-depth analysis of WES-data. The combined detection of small mutations and CNVs makes WES an attractive diagnostic test for genetically heterogeneous disorders.

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