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Human Mutation

Patricia Yuste-Checa, Sandra Brasil, Alejandra Gámez, Jarl Underhaug, Lourdes R Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Aurora Martinez, Belén Pérez
The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low molecular weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2...
October 24, 2016: Human Mutation
Raffaele Palmirotta, Domenica Lovero, Erica Silvestris, Valeria Simone, Laura Lanotte, Davide Quaresmini, Franco Silvestris
No abstract text is available yet for this article.
October 21, 2016: Human Mutation
Robbert D A Weren, Arjen R Mensenkamp, Michiel Simons, Astrid Eijkelenboom, Aisha S Sie, Hicham Ouchene, Monique van Asseldonk, Encarna B Gomez-Garcia, Marinus J Blok, Joanne A de Hullu, Marcel R Nelen, Alexander Hoischen, Johan Bulten, Bastiaan B J Tops, Nicoline Hoogerbrugge, En Marjolijn J L Ligtenberg
With the recent introduction of Poly(ADP-ribose) polymerase (PARP) inhibitors, a promising novel therapy has become available for ovarian carcinoma patients with inactivating BRCA1 or BRCA2 mutations in their tumour. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumour is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, we have developed a single molecule molecular inversion probe (smMIP)-based targeted next generation sequencing (NGS) approach...
October 21, 2016: Human Mutation
Jacopo Celli, Gudrun Rappold, Beate Niesler
Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3 A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions...
October 20, 2016: Human Mutation
Elizabeth S Barrie, Katherine Hartmann, Sung-Ha Lee, John T Frater, Michal Seweryn, Danxin Wang, Wolfgang Sadee
Functionally related genes often cluster into a genome region under coordinated regulation, forming a local regulome. To understand regulation of the CHRNA5/CHRNA3/CHRNB4 nicotinic receptor gene cluster, we integrate large-scale RNA expression data (brain and peripheral) from GTEx (Genotype Tissue Expression), clinical associations (GRASP) and linkage disequilibrium data (1,000 Genomes) to find candidate SNPs representing independent regulatory variants. CHRNA3, CHRNA5, CHRNB4 mRNAs, and a well-expressed CHRNA5 antisense RNA (RP11-650L12...
October 19, 2016: Human Mutation
Emilia Niemiec, Pascal Borry, Wim Pinxten, Heidi Carmen Howard
Whole exome sequencing (WES) and whole genome sequencing (WGS) have become increasingly available in the research and clinical settings and are now also being offered by direct-to-consumer (DTC) genetic testing (GT) companies. This offer can be perceived as amplifying the already identified concerns regarding adequacy of informed consent (IC) for both WES/WGS and the DTC GT context. We performed a qualitative content analysis of Websites of four companies offering WES/WGS DTC regarding the following elements of IC: pre-test counseling, benefits and risks, and incidental findings (IFs)...
October 5, 2016: Human Mutation
Walid Abi Habib, Frederic Brioude, Salah Azzi, Jennifer Salem, Cristina Das Neves, Claire Personnier, Sandra Chantot-Bastaraud, Boris Keren, Yves Le Bouc, Madeleine Harbison, Irene Netchine
The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann Syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients...
October 4, 2016: Human Mutation
Fu Xiong, Zhisong Ji, Yanhui Liu, Yu Zhang, Lingling Hu, Qi Yang, Qinwei Qiu, Lingfeng Zhao, Dong Chen, Zhihui Tian, Xuan Shang, Leitao Zhang, Xiaofeng Wei, Cuixian Liu, Qiuxia Yu, Meichao Zhang, Jing Cheng, Jun Xiong, Dongri Li, Xiuhua Wu, Huijun Yuan, Wenqing Zhang, Xiangmin Xu
Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p...
September 29, 2016: Human Mutation
Zhongshan Li, Zhenwei Liu, Yi Jiang, Denghui Chen, Xia Ran, Zhong Sheng Sun, Jinyu Wu
Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic sequence variants prioritizations from clinical exome sequencing (CES) variant data of single individual or family. The mirVAFC is able to comprehensively annotate sequence variants, filter out most irrelevant variants using custom criteria, classify variants into different categories as for estimated pathogenicity, and lastly provide pathogenic variants prioritizations based on classifications and mutation effects...
September 27, 2016: Human Mutation
Samiha S Shaikh, Ya-Chun Chen, Sally-Anne Halsall, Michael S Nahorski, Kiyoyuki Omoto, Gareth T Young, Anne Phelan, Christopher Geoffrey Woods
Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. Here, we studied a cohort of seven patients with HSAN IV and describe a comprehensive functional analysis of seven novel NTRK1 missense mutations, c.1550G>A, c.1565G>A, c.1970T>C, c.2096T>C, c.2254T>A, c.2288G>C, c.2311C>T, corresponding to p.G517E, p.G522E, p.L657P, p.I699T, p.C752S, p.C763S and p.R771C, all of which were predicted pathogenic by in-silico analysis...
September 27, 2016: Human Mutation
Daniele Raimondi, Gabriele Orlando, Joris Messens, Wim F Vranken
Cysteines are among the rarest amino acids in nature, and are both functionally and structurally very important for proteins. The ability of cysteines to form disulfide bonds is especially relevant, both for constraining the folded state of the protein and for performing enzymatic duties. But how does the variation record of human proteins reflect their functional importance and structural role, especially with regard to deleterious mutations? We created HUMCYS, a manually curated dataset of single amino acid variants that (1) have a known disease/neutral phenotypic outcome and (2) cause the loss of a cysteine, in order to investigate how mutated cysteines relate to structural aspects such as surface accessibility and cysteine oxidation state...
September 26, 2016: Human Mutation
Koutaro Yokote, Sirisak Chanprasert, Lin Lee, Katharina Eirich, Minoru Takemoto, Aki Watanabe, Naoko Koizumi, Davor Lessel, Takayasu Mori, Fuki M Hisama, Paula D Ladd, Brad Angle, Hagit Baris, Kivanc Cefle, Sukru Palanduz, Sukru Ozturk, Antoinette Chateau, Kentaro Deguchi, T K M Easwar, Antonio Federico, Amy Fox, Theresa A Grebe, Beverly Hay, Sheela Nampoothiri, Karen Seiter, Elizabeth Streeten, Raul E Piña-Aguilar, Gemma Poke, Martin Poot, Renata Posmyk, George M Martin, Christian Kubisch, Detlev Schindler, Junko Oshima
Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature...
September 26, 2016: Human Mutation
Cyril Burin-des-Roziers, Pierre-Raphael Rothschild, Valérie Layet, Jian-Min Chen, Tiffany Ghiotti, Céline Leroux, Frans P M Cremers, Antoine P Brézin, Sophie Valleix
Wagner disease is a rare non-syndromic autosomal dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease-associated splice mutations. Next-generation sequencing, quantitative real-time PCR, and long-range PCR, identified two deletions (3.4 kb and 10.5 kb) removing at least one exon-intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms...
September 26, 2016: Human Mutation
Serban Radian, Yoan Diekmann, Plamena Gabrovska, Brendan Holland, Lisa Bradley, Helen Wallace, Karen Stals, Anna-Marie Bussell, Karen McGurren, Martin Cuesta, Anthony W Ryan, Maria Herincs, Laura C Hernández-Ramírez, Aidan Holland, Jade Samuels, Elena Daniela Aflorei, Sayka Barry, Judit Dénes, Ida Pernicova, Craig E Stiles, Giampaolo Trivellin, Ronan McCloskey, Michal Ajzensztejn, Noina Abid, Scott A Akker, Moises Mercado, Mark Cohen, Rajesh V Thakker, Stephanie Baldeweg, Ariel Barkan, Madalina Musat, Miles Levy, Stephen M Orme, Martina Unterländer, Joachim Burger, Ajith V Kumar, Sian Ellard, Joseph McPartlin, Ross McManus, Gerard J Linden, Brew Atkinson, David J Balding, Amar Agha, Chris J Thompson, Steven J Hunter, Mark G Thomas, Patrick J Morrison, Márta Korbonits
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304(*) (or p.R304(*) ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304(*) carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0...
September 21, 2016: Human Mutation
Justine Lerat, Laurence Jonard, Natalie Loundon, Sophie Christin-Maitre, Didier Lacombe, Cyril Goizet, Cécile Rouzier, Lionel Van Maldergem, Souad Gherbi, Eréa-Nöel Garabedian, Jean-Paul Bonnefont, Philippe Touraine, Isabelle Mosnier, Arnold Munnich, Françoise Denoyelle, Sandrine Marlin
Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family...
September 21, 2016: Human Mutation
Amélie Pinard, David Salgado, Jean-Pierre Desvignes, Ghadi Rai, Nadine Hanna, Pauline Arnaud, Céline Guien, Maria Martinez, Laurence Faivre, Guillaume Jondeau, Catherine Boileau, Stéphane Zaffran, Christophe Béroud, Gwenaëlle Collod-Béroud
High-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes...
September 20, 2016: Human Mutation
Roel H P Wouters, Rhodé M Bijlsma, Margreet G E M Ausems, Johannes J M van Delden, Emile E Voest, Annelien L Bredenoord
Ever since genetic testing is possible for specific mutations, ethical debate has sparked on the question of whether professionals have a duty to warn not only patients but also their relatives that might be at risk for hereditary diseases. As next generation sequencing swiftly finds its way into clinical practice, the question who is responsible for conveying unsolicited findings to family members becomes increasingly urgent. Traditionally, there is a strong emphasis on the duties of the professional in this debate...
September 20, 2016: Human Mutation
Christophe Beroud, Stanley I Letovsky, Corey D Braastad, Sandrine M Caputo, Olivia Beaudoux, Yves Jean Bignon, Brigitte Bressac- De Paillerets, Myriam Bronner, Crystal M Buell, Gwenaëlle Collod-Béroud, Florence Coulet, Nicolas Derive, Christina Divincenzo, Christopher D Elzinga, Céline Garrec, Claude Houdayer, Izabela Karbassi, Sarab Lizard, Angela Love, Danièle Muller, Narasimhan Nagan, Camille R Nery, Ghadi Rai, Françoise Revillion, David Salgado, Nicolas Sévenet, Olga Sinilnikova, Hagay Sobol, Dominique Stoppa-Lyonnet, Christine Toulas, Edwin Trautman, Dominique Vaur, Paul Vilquin, Katelyn S Weymouth, Alecia Willis, Marcia Eisenberg, Charles M Strom
As next generation sequencing (NGS) increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a critical part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This paper describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories...
September 16, 2016: Human Mutation
Rossella Tricarico, Mariann Kasela, Cristina Mareni, Bryony A Thompson, Aurélie Drouet, Lucia Staderini, Greta Gorelli, Francesca Crucianelli, Valentina Ingrosso, Jukka Kantelinen, Laura Papi, Maria De Angioletti, Margherita Berardi, Pascaline Gaildrat, Omar Soukarieh, Daniela Turchetti, Alexandra Martins, Amanda B Spurdle, Minna Nyström, Maurizio Genuardi
Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity...
September 15, 2016: Human Mutation
Maki Igarashi, Kei Takasawa, Akiko Hakoda, Junko Kanno, Shuji Takada, Mami Miyado, Takashi Baba, Ken-Ichirou Morohashi, Toshihiro Tajima, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Ryohei Sekido, Tsutomu Ogata, Kenichi Kashimada, Maki Fukami
The role of monogenic mutations in the development of 46,XX testicular/ovotesticular disorders of sex development (DSD) remains speculative. Although mutations in NR5A1 are known to cause 46,XY gonadal dysgenesis and 46,XX ovarian insufficiency, such mutations have not been implicated in testicular development of 46,XX gonads. Here, we identified identical NR5A1 mutations in two unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The p.Arg92Trp mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals...
September 9, 2016: Human Mutation
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