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Human Mutation

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https://www.readbyqxmd.com/read/27883256/detecting-agg-interruptions-in-male-and-female-fmr1-premutation-carriers-by-single-molecule-sequencing
#1
Simon Ardui, Valerie Race, Alena Zablotskaya, Matthew S Hestand, Hilde Van Esch, Koenraad Devriendt, Gert Matthijs, Joris R Vermeesch
The FMR1 gene contains an unstable CGG repeat in its 5' untranslated region. Premutation alleles range between 55 and 200 repeat units and confer a risk for developing fragile X-associated tremor/ataxia syndrome or fragile X-associated primary ovarian insufficiency. Furthermore, the premutation allele often expands to a full mutation during female germline transmission giving rise to the fragile X syndrome. The risk for a premutation to expand depends mainly on the number of CGG units and the presence of AGG interruptions in the CGG repeat...
November 24, 2016: Human Mutation
https://www.readbyqxmd.com/read/27864847/diagnostic-targeted-resequencing-in-349-patients-with-drug-resistant-pediatric-epilepsies-identifies-causative-mutations-in-30-different-genes
#2
Elena Parrini, Carla Marini, Davide Mei, Anna Galuppi, Elena Cellini, Daniela Pucatti, Laura Chiti, Domenico Rutigliano, Claudia Bianchini, Simona Virdò, Dalila De Vita, Stefania Bigoni, Carmen Barba, Francesco Mari, Martino Montomoli, Tiziana Pisano, Anna Rosati, Renzo Guerrini
Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6...
November 19, 2016: Human Mutation
https://www.readbyqxmd.com/read/27859906/human-recq-helicase-pathogenic-variants-population-variation-and-missing-diseases
#3
Wenqing Fu, Alessio Ligabue, Kai J Rogers, Joshua M Akey, Raymond J Monnat
Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN and RECQL4 cause Bloom, Werner and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique basepair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4 and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies...
November 17, 2016: Human Mutation
https://www.readbyqxmd.com/read/27862604/whole-genome-sequencing-of-cytogenetically-balanced-chromosome-translocations-identifies-potentially-pathological-gene-disruptions-and-highlights-the-importance-of-microhomology-in-the-mechanism-of-formation
#4
Daniel Nilsson, Maria Pettersson, Peter Gustavsson, Alisa Förster, Wolfgang Hofmeister, Josephine Wincent, Vasilios Zachariadis, Britt-Marie Anderlid, Ann Nordgren, Outi Mäkitie, Valtteri Wirta, Max Käller, Francesco Vezzi, James R Lupski, Magnus Nordenskjöld, Elisabeth Syk Lundberg, Claudia M B Carvalho, Anna Lindstrand
Most balanced translocations are thought to result mechanistically from non-homologous endjoining (NHEJ) or, in rare cases of recurrent events, by nonallelic homologous recombination (NAHR). Here, we use low coverage mate pair whole genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers...
November 16, 2016: Human Mutation
https://www.readbyqxmd.com/read/27860035/a-cell-type-specific-expression-signature-predicts-haploinsufficient-autism-susceptibility-genes
#5
Chaolin Zhang, Yufeng Shen
Recent studies have identified many genes with rare de novo mutations in autism, but a limited number of these have been conclusively established as disease-susceptibility genes due to lack of recurrence and confounding background mutations. Such extreme genetic heterogeneity severely limits recurrence-based statistical power even in studies with a large sample size. Here we use cell-type specific expression profiles to differentiate mutations in autism patients from those in unaffected siblings. We report a gene expression signature in different neuronal cell types shared by genes with likely gene disrupting (LGD) mutations in autism cases...
November 16, 2016: Human Mutation
https://www.readbyqxmd.com/read/27862579/mutations-in-trappc11-are-associated-with-a-congenital-disorder-of-glycosylation
#6
Leslie Matalonga, Miren Bravo, Carla Serra Peinado, Elisabeth García-Pelegrí, Olatz Ugarteburu, Silvia Vidal, Maria Llambrich, Ester Quintana, Pedro Fuster-Jorge, Maria Nieves Gonzalez-Bravo, Sergi Beltran, Joaquin Dopazo, Francisco Garcia-Garcia, François Foulquier, Gert Matthijs, Philippa Mills, Antonia Ribes, Gustavo Egea, Paz Briones, Frederic Tort, Marisa Girós
Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the Golgi apparatus due to mutations in TRAPPC11, a subunit of the TRAPPIII complex...
November 10, 2016: Human Mutation
https://www.readbyqxmd.com/read/27862583/how-to-define-pathogenicity-health-and-disease
#7
Mauno Vihinen
Scientific and clinical communities produce ever increasing amounts of data and details about health and disease. Our ability to understand and utilize this information is limited due to imprecise language and lack of well-defined concepts. This problem involves also the principal concepts of health, disease and pathogenicity. Here, a systematic model is presented for pathogenicity, as well as for health and disease. It has three components: extent, modulation and severity, which jointly define the continuum of pathogenicity...
November 9, 2016: Human Mutation
https://www.readbyqxmd.com/read/27805744/clinical-and-molecular-characteristics-of-slc16a2-mct8-mutations-in-three-families-with-the-allan-herndon-dudley-syndrome
#8
Francesca Novara, Stefan Groeneweg, Elena Freri, Margherita Estienne, Paolo Reho, Sara Matricardi, Barbara Castellotti, W Edward Visser, Orsetta Zuffardi, Theo J Visser
Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype...
November 2, 2016: Human Mutation
https://www.readbyqxmd.com/read/27804176/comparison-of-bioinformatics-prediction-molecular-modeling-and-functional-analyses-of-foxc1-mutations-in-patients-with-axenfeld-rieger-syndrome
#9
Morteza Seifi, Tim Footz, Sherry A M Taylor, Michael A Walter
Mutations in the forkhead box C1 gene (FOXC1) cause Axenfeld-Rieger syndrome (ARS). Here, we investigated the effect of four ARS missense variants on FOXC1 structure and function, and examined the predictive value of four in silico programs for all 31 FOXC1 missense variants identified to date. Molecular modeling of the FOXC1 forkhead domain predicts that c.402G> A (p.C135Y) alters FOXC1's structure. In contrast, c.378A> G (p.H128R) and c.481A> G (p.M161V) are not predicted to change FOXC1's structure...
November 2, 2016: Human Mutation
https://www.readbyqxmd.com/read/27790796/functional-characterization-and-rescue-of-a-deep-intronic-mutation-in-ocrl-gene-responsible-for-lowe-syndrome
#10
John Rendu, Rodrick Montjean, Charles Coutton, Mohnish Suri, Gaetan Chicanne, Anne Petiot, Julie Brocard, Didier Grunwald, France Pietri Rouxel, Bernard Payrastre, Joel Lunardi, Olivier Dorseuil, Isabelle Marty, Julien Fauré
Dent-2 disease and Lowe syndrome are two pathologies caused by mutations in inositol polyphosphate 5-phosphatase OCRL gene. Both conditions share proximal tubulopathy evolving to chronic kidney failure. Lowe syndrome is in addition defined by a bilateral congenital cataract, intellectual disability, and hypotonia. The pathology evolves in two decades to a severe condition with renal complications and a fatal issue. We describe here a proof of principle for a targeted gene therapy on a mutation of the OCRL gene that is associated with Lowe syndrome...
October 28, 2016: Human Mutation
https://www.readbyqxmd.com/read/27774737/pharmacological-chaperoning-a-potential-treatment-for-pmm2-cdg
#11
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
https://www.readbyqxmd.com/read/27768236/characterization-of-a-rare-nonpathogenic-methylenetetrahydrofolatereductase-mthfr-gene-mutation-p-lys215del-in-a-southern-italian-family
#12
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
https://www.readbyqxmd.com/read/27767231/novel-brca1-and-brca2-tumor-test-as-basis-for-treatment-decisions-and-referral-for-genetic-counselling-of-patients-with-ovarian-carcinomas
#13
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, Marjolijn J L Ligtenberg
With the recent introduction of Poly(ADP-ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor 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
https://www.readbyqxmd.com/read/27763704/the-human-serotonin-type-3-receptor-gene-htr3a-e-allelic-variant-database
#14
Jacopo Celli, Gudrun Rappold, Beate Niesler
Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-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
https://www.readbyqxmd.com/read/27758088/the-chrna5-chrna3-chrnb4-nicotinic-receptor-regulome-genomic-architecture-regulatory-variants-and-clinical-associations
#15
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
https://www.readbyqxmd.com/read/27701793/11p15-icr1-partial-deletions-associated-with-igf2-h19-dmr-hypomethylation-and-silver-russell-syndrome
#16
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
https://www.readbyqxmd.com/read/27680507/mutation-in-ssuh2-causes-autosomal-dominant-dentin-dysplasia-type-i
#17
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
https://www.readbyqxmd.com/read/27676360/mirvafc-a-web-server-for-prioritizations-of-pathogenic-sequence-variants-from-exome-sequencing-data-via-classifications
#18
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
https://www.readbyqxmd.com/read/27676246/a-comprehensive-functional-analysis-of-ntrk1-missense-mutations-causing-hereditary-sensory-and-autonomic-neuropathy-type-iv-hsan-iv
#19
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
https://www.readbyqxmd.com/read/27667481/investigating-the-molecular-mechanisms-behind-uncharacterized-cysteine-losses-from-prediction-of-their-oxidation-state
#20
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
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