Human Mutation

Cover image for Vol. 34 Issue 9

September 2013

Volume 34, Issue 9

Pages iv–iv, 1183–1311, E2393–E2402

  1. Features

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
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    2. You have free access to this content
  2. Special Articles

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. You have free access to this content
  3. Informatics

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. HAPLOFIND: A New Method for High-Throughput mtDNA Haplogroup Assignment (pages 1189–1194)

      Dario Vianello, Federica Sevini, Gastone Castellani, Laura Lomartire, Miriam Capri and Claudio Franceschi

      Version of Record online: 12 JUN 2013 | DOI: 10.1002/humu.22356

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      HaploFind is a pipeline that combines previous resources with a newly developed algorithm capable of efficiently and easily classifying new mtDNA sequences according to PhyloTree nomenclature. A weighted tree, produced taking into account each haplogroup pattern conservation, represents the method foundation.

      Exploiting cutting edge technologies, we built a high-throughput pipeline for the analysis of mtDNA sequences that can be quickly updated to follow the ever-changing nomenclature.

      HaploFind is freely accessible at the address: https://haplofind.unibo.it.

  4. Rapid Communications

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. The Syndrome of Microcornea, Myopic Chorioretinal Atrophy, and Telecanthus (MMCAT) Is Caused by Mutations in ADAMTS18 (pages 1195–1199)

      Mohammed A. Aldahmesh, Muneera J. Alshammari, Arif O. Khan, Jawahir Y. Mohamed, Fatimah A. Alhabib and Fowzan S. Alkuraya

      Version of Record online: 19 JUL 2013 | DOI: 10.1002/humu.22374

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      Alkuraya and colleagues report the genetic etiology of a novel ocular syndrome that is characterized primarily by cataract, myopia and chorioretinal atrophy. Multiple consanguineous families mapped to a single locus on chr16q23.1 in which the authors identified several likely pathogenic mutations in ADAMTS18.

    2. You have full text access to this OnlineOpen article
      The Sac1 Domain of SYNJ1 Identified Mutated in a Family with Early-Onset Progressive Parkinsonism with Generalized Seizures (pages 1200–1207)

      Catharine E. Krebs, Siamak Karkheiran, James C. Powell, Mian Cao, Vladimir Makarov, Hossein Darvish, Gilbert Di Paolo, Ruth H. Walker, Gholam Ali Shahidi, Joseph D. Buxbaum, Pietro De Camilli, Zhenyu Yue and Coro Paisán-Ruiz

      Version of Record online: 19 JUL 2013 | DOI: 10.1002/humu.22372

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      In this study we identified a mutation in synaptojanin 1 as a cause of early-onset progressive Parkinsonism and generalized seizures. This mutation impaired the phosphatase activity of synaptojanin 1 against its Sac1 domain substrates in vitro, suggesting that defects in phosphoinositide metabolism at synapse may play an important role in the development of Parkinsonism. This finding opens new avenues of investigation in the field of Parkinson research and suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.

    3. Mutation in the SYNJ1 Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism (pages 1208–1215)

      Marialuisa Quadri, Mingyan Fang, Marina Picillo, Simone Olgiati, Guido J. Breedveld, Josja Graafland, Bin Wu, Fengping Xu, Roberto Erro, Marianna Amboni, Sabina Pappatà, Mario Quarantelli, Grazia Annesi, Aldo Quattrone, Hsin F. Chien, Egberto R. Barbosa, The International Parkinsonism Genetics Network, Ben A. Oostra, Paolo Barone, Jun Wang and Vincenzo Bonifati

      Version of Record online: 6 AUG 2013 | DOI: 10.1002/humu.22373

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      By homozygosity mapping and exome sequencing in an Italian consanguineous family with early-onset Parkinsonism, we identified a disease-segregating homozygous SYNJ1 mutation.

      SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase, essential for the post-endocytic recycling of synaptic vesicles. This work delineates a novel form of Mendelian Parkinsonism and provides further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. We also provide a detailed description of the clinical phenotype, and structural and functional neuroimaging of this novel form.

    4. Large Numbers of Genetic Variants Considered to be Pathogenic are Common in Asymptomatic Individuals (pages 1216–1220)

      Christopher A. Cassa, Mark Y. Tong and Daniel M. Jordan

      Version of Record online: 5 AUG 2013 | DOI: 10.1002/humu.22375

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      We find that 8.5% of variants in a large pathogenic mutation database (HGMD) are present in at least one individual in the 1000 Genomes Project. Many of these pathogenic variants are common: there are 3,744 variants with minor allele frequency (MAF) ≥ 0.01 (4.6%) and 2,837 variants with MAF ≥ 0.05 (3.5%). This indicates that many of these variants may be erroneous findings, have lower penetrance than previously expected, or are associations with low effect size.

  5. Brief Reports

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome (pages 1221–1225)

      Rajvir Singh, Emily Smith, Mohsen Fathzadeh, Wenzhong Liu, Gwang-Woong Go, Lakshman Subrahmanyan, Saeed Faramarzi, William McKenna and Arya Mani

      Version of Record online: 18 JUN 2013 | DOI: 10.1002/humu.22360

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      LRP6 is a member of LDL receptor family of proteins, which is widely known for its diverse functions as a coreceptor for the Wnt family of proteins during embryonic development. Recent studies have shown its involvement in regulation of vascular integrity, blood pressure, plasmaglucose and lipids and bone mineralization in adult life.

    2. Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects (pages 1226–1230)

      Sheng-Wei Chang, Mona Mislankar, Chaitali Misra, Nianyuan Huang, Daniel G. DaJusta, Steven M. Harrison, Kim L. McBride, Linda A. Baker and Vidu Garg

      Version of Record online: 11 JUL 2013 | DOI: 10.1002/humu.22366

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      We identified a patient with complex congenital heart disease (CHD) who harbored a heterozygous deletion of FOXP1 and subsequently found two patients with CHD who had a heterozygous c.1702C>T variant that predicted a potentially deleterious mutation (p.P568S). The mutant Foxp1 displayed functional deficits in cell-based assays suggesting that FOXP1 mutations are associated with CHD.

  6. Research Articles

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. Somatic Alterations Contributing to Metastasis of a Castration-Resistant Prostate Cancer (pages 1231–1241)

      Michael L. Nickerson, Kate M. Im, Kevin J. Misner, Wei Tan, Hong Lou, Bert Gold, David W. Wells, Hector C. Bravo, Karin M. Fredrikson, Timothy T. Harkins, Patrice Milos, Berton Zbar, W. Marston Linehan, Meredith Yeager, Thorkell Andresson, Michael Dean and G. Steven Bova

      Version of Record online: 3 JUN 2013 | DOI: 10.1002/humu.22346

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      We sequenced the exomes of five metastatic tumors and healthy kidney tissue from a mCRPC index case to identify lesions associated with disease progression and metastasis. The majority of somatic nonsynonymous variants were present in all metastases and only a subset was observed in the primary tumor. Somatic variants in individual tumors permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of lesions. TET2 alteration or loss may define a subset of mCRPC.

    2. Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser–Winter Syndrome (pages 1242–1249)

      Jennifer J. Johnston, Kuo-Kuang Wen, Kim Keppler-Noreuil, Melissa McKane, Jessica L. Maiers, Alexander Greiner, Julie C. Sapp, NIH Intramural Sequencing Center, Kris A. DeMali, Peter A. Rubenstein and Leslie G. Biesecker

      Version of Record online: 28 MAY 2013 | DOI: 10.1002/humu.22350

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      Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We present clinical and exome findings in a patient with atypical Baraitser–Winter syndrome due to a mutation in ACTB. Functional characterization of the mutant actin molecule both in vivo and in vitro suggests altered polymerization dynamics contributed to the phenotype.

    3. Chimeric Negative Regulation of p14ARF and TBX1 by a t(9;22) Translocation Associated with Melanoma, Deafness, and DNA Repair Deficiency (pages 1250–1259)

      Xiaohui Tan, Sarah L. Anzick, Sikandar G. Khan, Takahiro Ueda, Gary Stone, John J. DiGiovanna, Deborah Tamura, Daniel Wattendorf, David Busch, Carmen C. Brewer, Christopher Zalewski, John A. Butman, Andrew J. Griffith, Paul S. Meltzer and Kenneth H. Kraemer

      Version of Record online: 3 JUN 2013 | DOI: 10.1002/humu.22354

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      We studied a patient with melanoma, DNA repair deficiency, and deafness due to malformed inner ears who had a novel balanced t(9;22) translocation. Sequencing this break region served as a “Rosetta stone” permitting identification of a new gene, FAM230A, within a gap region on chromosome 22. The chimeric p14ARF-FAM230A gene appears to play an important dominant negative regulatory role in melanoma induction and ear development in this patient.

    4. You have full text access to this OnlineOpen article
      Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease (pages 1260–1268)

      Emma L. Blakely, John W. Yarham, Charlotte L. Alston, Kate Craig, Joanna Poulton, Charlotte Brierley, Soo-Mi Park, Andrew Dean, John H. Xuereb, Kirstie N. Anderson, Alistair Compston, Chris Allen, Saba Sharif, Peter Enevoldson, Martin Wilson, Simon R. Hammans, Douglass M. Turnbull, Robert McFarland and Robert W. Taylor

      Version of Record online: 14 AUG 2013 | DOI: 10.1002/humu.22358

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      We describe novel mitochondrial tRNA point mutations in nine families associated with a diverse range of clinical presentations, providing functional evidence to classify six of these variants as definitely pathogenic, with the remaining three classed as possibly pathogenic. Our report adds to the large number of mitochondrial tRNA variants associated with disease and confirms mitochondrial tRNA mutations as an important subgroup of human genetic disorders.

    5. Novel CLCNKB Mutations Causing Bartter Syndrome Affect Channel Surface Expression (pages 1269–1278)

      Mathilde Keck, Olga Andrini, Olivier Lahuna, Johanna Burgos, L. Pablo Cid, Francisco V. Sepúlveda, Sébastien L‘Hoste, Anne Blanchard, Rosa Vargas-Poussou, Stéphane Lourdel and Jacques Teulon

      Version of Record online: 12 JUN 2013 | DOI: 10.1002/humu.22361

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      Bartter syndrome type 3, a hereditary disease characterized by renal salt wasting, is associated with mutations in the CLCNKB gene encoding the chloride channel ClC-Kb, which mediates the basolateral step of chloride absorption in the distal nephron. Investigating the functional consequences of seven mutations in Xenopus laevis oocytes, we identified two classes of mutants: mutants displaying no electrical activity and low total protein expression, and partially conducting mutants with unaltered protein abundance.

    6. Kuskokwim Syndrome, a Recessive Congenital Contracture Disorder, Extends the Phenotype of FKBP10  Mutations (pages 1279–1288)

      Aileen M. Barnes, Geraldine Duncan, MaryAnn Weis, William Paton, Wayne A. Cabral, Edward L. Mertz, Elena Makareeva, Michael J. Gambello, Felicitas L. Lacbawan, Sergey Leikin, Andrzej Fertala, David R. Eyre, Sherri J. Bale and Joan C. Marini

      Version of Record online: 8 JUL 2013 | DOI: 10.1002/humu.22362

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      We identified a homozygous 3-nucleotide deletion in FKBP10 (c.877_879delTAC) in Kuskokwim syndrome (KS), an autosomal recessive congenital contracture disorder; this complements the FKBP10 phenotypes of osteogenesis imperfecta and Bruck syndrome. KS fibroblast collagen has 2-10% hydroxylation of the telopeptide lysine crucial for cross-linking in matrix, vs 60% in controls, causing reduced collagen deposition and looser fibril packing. We propose that FKBP10 mutations affect collagen by ablating support for collagen telopeptide hydroxylation by LH2, thus decreasing collagen crosslinks in bone matrix.

    7. Functional Interaction Between SNPs and Microsatellite in the Transcriptional Regulation of Insulin-Like Growth Factor 1 (pages 1289–1297)

      Holly Y. Chen, Wei Huang, Vincent H. K. Leung, Simon L. M. Fung, Suk Ling Ma, Hongling Jiang and Nelson L. S. Tang

      Version of Record online: 8 JUL 2013 | DOI: 10.1002/humu.22363

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      Investigation of the transcriptional activity of IGF1 promoter fragments showed a determining role of the microsatellite in the regulation of gene expression, which was contributed by the length of the microsatellite and its interaction with nearby SNPs. This study provides a biological insight into the phenomena of epistasis observed in epidemiology studies.

  7. Methods

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. 0.5 Mb Array as a First-Line Prenatal Cytogenetic Test in Cases without Ultrasound Abnormalities and Its Implementation in Clinical Practice (pages 1298–1303)

      Malgorzata I. Srebniak, Lisanne Mout, Diane Van Opstal and Robert-Jan H. Galjaard

      Version of Record online: 6 JUN 2013 | DOI: 10.1002/humu.22355

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      Based on our experience and the results presented here, we recommend performing rapid array testing as a first-tier test in all cases referred for invasive prenatal diagnosis by using the same array platform and performing high resolution analysis in cases of ultrasound abnormalities and 0.5Mb analysis for other indications. A 0.5Mb resolution shows a high diagnostic potential and significantly minimizes the number of VOUS. It can detect the well-known microdeletion syndromes including the atypical 22q11 microdeletion presented on the image.

    2. Rapid Multiplexed Genotyping of Simple Tandem Repeats using Capture and High-Throughput Sequencing (pages 1304–1311)

      Audrey Guilmatre, Gareth Highnam, Christelle Borel, David Mittelman and Andrew J. Sharp

      Version of Record online: 17 JUN 2013 | DOI: 10.1002/humu.22359

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      We have developed a cost effective strategy for performing targeted enrichment of simple tandem repeats (STRs) that utilizes capture probes targeting the flanking sequences of STR, enabling specific capture of DNA fragments containing STRs for subsequent high-throughput sequencing. Targeting >6,000 STRs located within gene promoter regions, the figure shows the percentage of STRs successfully genotyped and mean depth of informative reads as a function of STR (G+C) content.

  8. Database In Brief

    1. Top of page
    2. Features
    3. Special Articles
    4. Informatics
    5. Rapid Communications
    6. Brief Reports
    7. Research Articles
    8. Methods
    9. Database In Brief
    1. You have free access to this content

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