Molecular Genetics & Genomic Medicine

Cover image for Vol. 4 Issue 2

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Maximilian Muenke, M.D., Deputy Editor: Suzanne Hart, Ph.D.

Online ISSN: 2324-9269

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  1. 1 - 19
  1. Original Articles

    1. You have full text access to this OnlineOpen article
      Pitfalls in genetic testing: the story of missed SCN1A mutations

      Tania Djémié, Sarah Weckhuysen, Sarah von Spiczak, Gemma L. Carvill, Johanna Jaehn, Anna-Kaisa Anttonen, Eva Brilstra, Hande S. Caglayan, Carolien G. de Kovel, Christel Depienne, Eija Gaily, Elena Gennaro, Beatriz G. Giraldez, Padhraig Gormley, Rosa Guerrero-López, Renzo Guerrini, Eija Hämäläinen, Corinna Hartmann, Laura Hernandez-Hernandez, Helle Hjalgrim, Bobby P. C. Koeleman, Eric Leguern, Anna-Elina Lehesjoki, Johannes R. Lemke, Costin Leu, Carla Marini, Jacinta M. McMahon, Davide Mei, Rikke S. Møller, Hiltrud Muhle, Candace T. Myers, Caroline Nava, Jose M. Serratosa, Sanjay M. Sisodiya, Ulrich Stephani, Pasquale Striano, Marjan J. A. van Kempen, Nienke E. Verbeek, Sunay Usluer, Federico Zara, Aarno Palotie, Heather C. Mefford, Ingrid E. Scheffer, Peter De Jonghe, Ingo Helbig, Arvid Suls and EuroEPINOMICS-RES Dravet working group

      Article first published online: 14 APR 2016 | DOI: 10.1002/mgg3.217

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      We explored to what extent inconsistencies between Sanger sequencing and next-generation sequencing affect the molecular diagnosis of patients. Hereto we focused on the analysis of mutations in SCN1A, the major gene implicated in Dravet syndrome and epilepsy. We illustrate the pitfalls of genetic screening technologies and most importantly provide evidence that SCN1A mutations are an even more frequent cause of Dravet syndrome than already anticipated.

  2. Editorial

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      A 2.5-year snapshot of Mendelian discovery

      Benjamin D. Solomon, Teresa Lee, Anh-Dao Nguyen and Tyra G. Wolfsberg

      Article first published online: 3 APR 2016 | DOI: 10.1002/mgg3.221

  3. Original Articles

    1. You have full text access to this OnlineOpen article
      Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability

      Wayne W.K. Lam, John J. Millichap, Dinesh C. Soares, Richard Chin, Ailsa McLellan, David R. FitzPatrick, Frances Elmslie, Melissa M. Lees, G. Bradley Schaefer, DDD study and Catherine M. Abbott

      Article first published online: 3 APR 2016 | DOI: 10.1002/mgg3.219

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      Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation; in one case the disorder is much less severe than in previously described individuals.

    2. You have full text access to this OnlineOpen article
      The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita

      Shahinaz M. Gadalla, Payal P. Khincha, Hormuzd A. Katki, Neelam Giri, Jason Y. Y. Wong, Stephen Spellman, Jack A. Yanovski, Joan C. Han, Immaculata De Vivo, Blanche P. Alter and Sharon A. Savage

      Article first published online: 20 MAR 2016 | DOI: 10.1002/mgg3.220

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      We conducted a study of the widely used, high throughput method of qPCR relative TL (RTL) to evaluate its diagnostic performance for dyskeratosis congenita. Our data show that RTL < 1st percentile for age failed to identify more than 60% of the patients (sensitivity=39%, specificity=98%). Test sensitivity improved when raising the cutoff point to the 10th percentile but this was at the expense of test specificity (sensitivity=74%, specificity=88%).

    3. You have full text access to this OnlineOpen article
      Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas

      Xiangqing Sun, Robert Elston, Gary W. Falk, William M. Grady, Ashley Faulx, Sumeet K. Mittal, Marcia I. Canto, Nicholas J. Shaheen, Jean S. Wang, Prasad G. Iyer, Julian A. Abrams, Joseph E. Willis, Kishore Guda, Sanford Markowitz, Jill S. Barnholtz-Sloan, Apoorva Chandar, Wendy Brock and Amitabh Chak

      Article first published online: 14 MAR 2016 | DOI: 10.1002/mgg3.211

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      We identified linkage regions on chromosomes 2q31, 12q23, and 15q26. Some of our linkage regions are consistent with reported genomic associations to BE and EAC. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to Barrett's esophagus and esophageal adenocarcinomas, and help focus the search for causal genes.

    4. You have full text access to this OnlineOpen article
      Computational assessment of feature combinations for pathogenic variant prediction

      Eva König, Johannes Rainer and Francisco S. Domingues

      Article first published online: 14 MAR 2016 | DOI: 10.1002/mgg3.214

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      We investigated which combination of existing methods, variant features, and gene features archived the best performance in the prediction of pathogenic variants. We found that combining the number of “biological process” Gene Ontology annotations of a gene with the methods PON-P2 and PROVEAN significantly improved prediction of pathogenic variants, outperforming all individual methods. Analysis of the Gene Ontology feature suggests that it is not a variant-dependent annotation bias but reflects the multifunctional nature of disease genes.

    5. You have full text access to this OnlineOpen article
      Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1–LGI1 signaling

      Rhalena A. Thomas, Amirthagowri Ambalavanan, Guy A. Rouleau and Philip A. Barker

      Article first published online: 11 MAR 2016 | DOI: 10.1002/mgg3.215

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      We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1, and observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W) and three novel LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M) and an intronic variant (g.897T>C) that likely leads to a protein truncation. Using cell-based assays we found that coding variants of NgR1 have a reduced ability to bind LGI1 and that NgR1 mutants are impaired in their ability to mediate RhoA activation.

    6. You have full text access to this OnlineOpen article
      Importance of nonsynonymous OCA2 variants in human eye color prediction

      Jeppe D. Andersen, Carlotta Pietroni, Peter Johansen, Mikkel M. Andersen, Vania Pereira, Claus Børsting and Niels Morling

      Article first published online: 11 MAR 2016 | DOI: 10.1002/mgg3.213

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      We showed that the two variants, rs7465330 and rs129119166 had a measurable effect on eye color variation.

    7. You have full text access to this OnlineOpen article
      Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction

      Caitlin A. Orsini, Barry Setlow, Michael DeJesus, Stacy Galaviz, Kimberly Loesch, Thomas Ioerger and Deeann Wallis

      Article first published online: 4 MAR 2016 | DOI: 10.1002/mgg3.207

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      LPHN3 has been associated with both ADHD and vulnerability to addiction. We evaluated a Lphn3 null mouse and observed changes in behavior that encompass both activity levels and reward motivation. We also observe altered serum calcium levels; neurite outgrowth; and neurotransmitter levels. Further, our data indicate that loss of Lphn3 leads to developmentally dynamic alterations in the transcriptome and suggest that cell adhesion molecules and calcium-dependent signaling proteins are affected. These transcriptomic and neuronal changes in structure and function are anticipated to affect the brain as a whole and further result in changes in behavior.

  4. Methods

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      A novel approach for next-generation sequencing of circulating tumor cells

      Stephanie S. Yee, David B. Lieberman, Tatiana Blanchard, JulieAnn Rader, Jianhua Zhao, Andrea B. Troxel, Daniel DeSloover, Alan J. Fox, Robert D. Daber, Bijal Kakrecha, Shrey Sukhadia, George K. Belka, Angela M. DeMichele, Lewis A. Chodosh, Jennifer J. D. Morrissette and Erica L. Carpenter

      Article first published online: 28 FEB 2016 | DOI: 10.1002/mgg3.210

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      The application of solid tumor next-generation sequencing (NGS) approaches to circulating tumor samples has been hampered by the low-input DNA available from rare circulating tumor cells (CTCs), and whole genome amplification (WGA) approaches used to generate sufficient input DNA are often incompatible with blood collection tube preservatives used to facilitate clinical sample batching. We developed a novel approach combining tumor cell isolation from preserved blood with Repli-G WGA and Illumina TruSeq Amplicon Cancer Panel-based NGS. We applied this approach to purified cell pools ranging from 10 to 1000 cells from three different cell lines to provide proof of concept of a clinically applicable workflow for real-time monitoring of patient tumor using noninvasive liquid biopsies.

  5. Original Articles

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      Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy

      Paul R. Freund, Yuri V. Sergeev and Ian M. MacDonald

      Article first published online: 28 FEB 2016 | DOI: 10.1002/mgg3.208

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      Choroideremia is an X-linked inherited retinal degeneration that causes nyctalopia, progressive loss of visual fields leading to loss of central visual acuity. This natural history study describes the onset and progression of these factors with respect to age and causative mutation in the CHM gene. No genotype–phenotype correlations existed within this study suggesting all genotypes could be included in future clinical trials of gene therapy in choroideremia.

    2. You have full text access to this OnlineOpen article
      Rothmund–Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene

      Aude-Annick Suter, Peter Itin, Karl Heinimann, Munaza Ahmed, Tazeen Ashraf, Helen Fryssira, Usha Kini, Pablo Lapunzina, Peter Miny, Mette Sommerlund, Mohnish Suri, Signe Vaeth, Pradeep Vasudevan and Sabina Gallati

      Article first published online: 24 FEB 2016 | DOI: 10.1002/mgg3.209

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      We report on genotype and phenotype data of a cohort of 44 index patients with clinically suspected Rothmund–Thomson syndrome (RTS) or related genodermatoses. We describe 23 different RECQL4 mutations including 10 novel and one homozygous novel USB1 (C16orf57) mutation as well as 31 RECQL4 and 8 USB1 sequence variants. Our study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families.

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      Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy

      Akl C. Fahed, Ruby Khalaf, Rony Salloum, Rabih R. Andary, Raya Safa, Inaam El-Rassy, Elie Moubarak, Sami T. Azar, Fadi F. Bitar and Georges Nemer

      Article first published online: 24 FEB 2016 | DOI: 10.1002/mgg3.203

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      Familial hypercholesterolemia in Lebanon is more frequent than other parts of the world because of high rates of consanguineous marriages. We hereby report that the p.Q136* LDLRAP1 variant is the second “Lebanese Allele” in our country. In addition, we report the first family with both LDLR and LDLRAP1 variants with different phenotypes between family members unexplained by their corresponding genotypes.

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      Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families

      Laura I. Escobar, Christopher Simian, Cyrielle Treard, Donia Hayek, Carolina Salvador, Norma Guerra, Mario Matos, Mara Medeiros, Sandra Enciso, María Dolores Camargo and Rosa Vargas-Poussou

      Article first published online: 14 FEB 2016 | DOI: 10.1002/mgg3.205

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      We identified the molecular defects in the genes ATP6V1B1 and ATP6V0A4 of nine nonconsanguineous Mexican families with dRTA.

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      Carrier screening by next-generation sequencing: health benefits and cost effectiveness

      Mohammad Azimi, Kyle Schmaus, Valerie Greger, Dana Neitzel, Robert Rochelle and Tuan Dinh

      Article first published online: 29 JAN 2016 | DOI: 10.1002/mgg3.204

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      We evaluated the cost effectiveness of carrier screening via next-generation DNA sequencing (NGS) versus the traditional genotyping approach by using a robust mathematical model to estimate carefully selected health and other outcomes associated with 14 genetic diseases that major medical societies recommend for screening. The model accounts for all decisions considered by available medical opinion and outcomes relevant to carrier screening and reproductive health, drawing insight from the published literature, available clinical opinion, and subject matter experts.

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      Mosaic ratio quantification of isochromosome 12p in Pallister–Killian syndrome using droplet digital PCR

      Katsunori Fujiki, Katsuhiko Shirahige, Maninder Kaur, Matthew A. Deardorff, Laura K. Conlin, Ian D. Krantz and Kosuke Izumi

      Article first published online: 20 JAN 2016 | DOI: 10.1002/mgg3.200

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      We report the utility of the droplet digital PCR system in quantifying the mosaic ratio of isochromosome 12p in Pallister–Killian syndrome. Droplet digital PCR should be considered as an effective tool for both clinical and research analytics to precisely quantify mosaic genomic copy number alterations or mosaic mutations.

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      Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population

      Barbara Triggs-Raine, Tamara Dyck, Kym M. Boycott, A. Micheil Innes, Carole Ober, Jillian S. Parboosingh, Alexis Botkin, Cheryl R. Greenberg and Elizabeth L. Spriggs

      Article first published online: 19 JAN 2016 | DOI: 10.1002/mgg3.206

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      Hutterites, a religious isolate located in North America, have a number of genetic disorders that are unique and/or over-represented. A diagnostic chip that simultaneously tests for 30 autosomal recessive disorders of significance to this population was developed and validated in partnership with Asper Biotech. We have determined that this diagnostic chip provides a sensitive and specific means for carrier testing and has the potential to provide information that may empower future decision making in the Hutterite community.

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      Sideroblastic anemia: functional study of two novel missense mutations in ALAS2

      Manuel Méndez, María-Isabel Moreno-Carralero, Marta Morado-Arias, María-Cristina Fernández-Jiménez, Silvia de la Iglesia Iñigo and María-José Morán-Jiménez

      Article first published online: 13 JAN 2016 | DOI: 10.1002/mgg3.202

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      The different types of anemia are distinguished by characteristic hematological parameters and cellular morphology. The genetic study allows a more precise diagnosis. We report four cases with sideroblastic anemia with mutations in the 5-aminolevulinate synthase (ALAS2) gene. The in silico analysis of mutations and the in vitro study to assess functional consequences of the two novel mutations, leads to suggest that novel ALAS2 mutations are responsible of the disease.

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      Capture-based next-generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing

      Jing Xie, Xiongxiong Lu, Xue Wu, Xiaoyi Lin, Chao Zhang, Xiaofang Huang, Zhili Chang, Xinjing Wang, Chenlei Wen, Xiaomei Tang, Minmin Shi, Qian Zhan, Hao Chen, Xiaxing Deng, Chenghong Peng, Hongwei Li, Yuan Fang, Yang Shao and Baiyong Shen

      Article first published online: 10 JAN 2016 | DOI: 10.1002/mgg3.201

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      In this study, we have developed and validated a next-generation sequencing (NGS)-based cancer genomic diagnosis targeting hundreds of prognosis and therapeutics relevant genes on multiple types of cancer and specimen. We have assessed analytical sensitivity, specificity, and accuracy of the assay. Also, we developed clinical-applicable analysis pipelines that are capable of detecting base substitutions, indels, and gene copy number variations (CNVs). Our study has shown that NGS-based molecular diagnosis is more sensitive and comprehensive to detect genomic alterations in cancer, and supports a direct clinical use for guiding targeted therapy.

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