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Missense variants & pathogenicity prediction

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https://www.readbyqxmd.com/read/29664915/accurate-prediction-of-functional-structural-and-stability-changes-in-pitx2-mutations-using-in-silico-bioinformatics-algorithms
#1
Morteza Seifi, Michael A Walter
Mutations in PITX2 have been implicated in several genetic disorders, particularly Axenfeld-Rieger syndrome. In order to determine the most reliable bioinformatics tools to assess the likely pathogenicity of PITX2 variants, the results of bioinformatics predictions were compared to the impact of variants on PITX2 structure and function. The MutPred, Provean, and PMUT bioinformatic tools were found to have the highest performance in predicting the pathogenicity effects of all 18 characterized missense variants in PITX2, all with sensitivity and specificity >93%...
2018: PloS One
https://www.readbyqxmd.com/read/29659569/targeted-next-generation-sequencing-identifies-functionally-deleterious-germline-mutations-in-novel-genes-in-early-onset-familial-prostate-cancer
#2
Paula Paulo, Sofia Maia, Carla Pinto, Pedro Pinto, Augusta Monteiro, Ana Peixoto, Manuel R Teixeira
Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4...
April 16, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29658579/identification-of-tyr-mutations-in-patients-with-oculocutaneous-albinism
#3
Wan Sun, Yanjie Shen, Shan Shan, Liyun Han, Yang Li, Zheng Zhou, Zilin Zhong, Jianjun Chen
Oculocutaneous albinism (OCA) is a set of autosomal recessive disorders characterized by hypopigmented hair, skin and eyes. Homozygous or compound heterozygous mutations in the tyrosinase (TYR) gene can cause OCA1, which is the most common and severe subtype of albinism. In the present study, 17 patients with non‑syndromic OCA were enrolled from eight provinces of China and were non‑consanguineous, with the exception of Patient 4000301. Total genomic DNA was isolated from peripheral blood. Screening was performed for the whole exons and their flanking regions of the TYR gene using Sanger sequencing and the pathogenicity of variants was predicted using in silico analysis...
April 13, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29656858/a-recurrent-de-novo-pacs2-heterozygous-missense-variant-causes-neonatal-onset-developmental-epileptic-encephalopathy-facial-dysmorphism-and-cerebellar-dysgenesis
#4
Heather E Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Heron, Katrina Tatton-Brown, Paul A van der Zwaag, Emilia K Bijlsma, Bryan L Krock, E Backer, Erik-Jan Kamsteeg, Margje Sinnema, Margot R F Reijnders, David Bearden, Amber Begtrup, Aida Telegrafi, Roelineke J Lunsing, Lydie Burglen, Gaetan Lesca, Megan T Cho, Lacey A Smith, Beth R Sheidley, Christelle Moufawad El Achkar, Phillip L Pearl, Annapurna Poduri, Cara M Skraban, Jennifer Tarpinian, Addie I Nesbitt, Dietje E Fransen van de Putte, Claudia A L Ruivenkamp, Patrick Rump, Nicolas Chatron, Isabelle Sabatier, Julitta De Bellescize, Laurent Guibaud, David A Sweetser, Jessica L Waxler, Klaas J Wierenga, Jean Donadieu, Vinodh Narayanan, Keri M Ramsey, Caroline Nava, Jean-Baptiste Rivière, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Ange-Line Bruel, Yannis Duffourd, Laurel Thomas, Stefan H Lelieveld, Janneke Schuurs-Hoeijmakers, Han G Brunner, Boris Keren, Julien Thevenon, Laurence Faivre, Gary Thomas, Christel Thauvin-Robinet
Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals...
April 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29610305/structural-dynamics-is-a-determinant-of-the-functional-significance-of-missense-variants
#5
Luca Ponzoni, Ivet Bahar
Accurate evaluation of the effect of point mutations on protein function is essential to assessing the genesis and prognosis of many inherited diseases and cancer types. Currently, a wealth of computational tools has been developed for pathogenicity prediction. Two major types of data are used to this aim: sequence conservation/evolution and structural properties. Here, we demonstrate in a systematic way that another determinant of the functional impact of missense variants is the protein's structural dynamics...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29580235/performance-of-in-silico-prediction-tools-for-the-classification-of-rare-brca1-2-missense-variants-in-clinical-diagnostics
#6
Corinna Ernst, Eric Hahnen, Christoph Engel, Michael Nothnagel, Jonas Weber, Rita K Schmutzler, Jan Hauke
BACKGROUND: The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer...
March 27, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29568937/genetic-analysis-of-sick-sinus-syndrome-in-a-family-harboring-compound-cacna1c-and-ttn-mutations
#7
Yao-Bin Zhu, Jie-Wei Luo, Fen Jiang, Gui Liu
Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual)...
March 16, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29528531/a-novel-heterozygous-variant-in-erlin2-causes-autosomal-dominant-pure-hereditary-spastic-paraplegia
#8
Siri Lynne Rydning, Ales Dudesek, Florian Rimmele, Claudia Funke, Stefanie Krüger, Saskia Biskup, Magnus D Vigeland, Hanne S Hjorthaug, Yngve Sejersted, Chantal Tallaksen, Kaja K Selmer, Christoph Kamm
BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSP) are clinically and genetically heterogenous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function predicted by bioinformatic prediction tools...
March 12, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/29522274/neurofibromin-nf1-genetic-variant-structure-function-analyses-using-a-full-length-mouse-cdna
#9
Deeann Wallis, Kairong Li, Hui Lui, Ke Hu, Mei-Jan Chen, Jing Li, Jungsoon Kang, Shamik Das, Bruce R Korf, Robert A Kesterson
Neurofibromatosis type 1 (NF1; MIM# 613113) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a >250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells...
March 9, 2018: Human Mutation
https://www.readbyqxmd.com/read/29522266/gene-panel-testing-of-5589-brca1-2-negative-index-patients-with-breast-cancer-in-a-routine-diagnostic-setting-results-of-the-german-consortium-for-hereditary-breast-and-ovarian-cancer
#10
Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang-Gohrke, Mateja Smogavec, Bernhard H F Weber, Nana Weber-Lassalle, Konstantin Weber-Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K Schmutzler, Eric Hahnen
The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing...
March 9, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29518881/-a-novel-vsx1-gene-mutation-identified-in-a-sporadic-keratoconus-patient-from-china
#11
T Guan, H J Wu, L J Zhang, D J Xu, L B Zheng, Y F Yao
Objective: To investigate the possibility of the visual system homeobox 1 (VSX1) gene as a candidate susceptibility gene for Chinese patients with sporadic keratoconus, and to identify sequence variants of the VSX1 gene in such patients. Methods: Cross-sectional study. Genomic DNA was extracted from the leukocytes in the peripheral venous blood of 50 patients with sporadic keratoconus and 50 control subjects without this ocular disorder. Five exons and the intron-exon splicing of the VSX1 gene were amplified by polymerase chain reaction (PCR)...
March 11, 2018: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
https://www.readbyqxmd.com/read/29518248/defective-mitochondrial-protease-lonp1-can-cause-classical-mitochondrial-disease
#12
Bradley Peter, Christie L Waddington, Monika Oláhová, Ewen W Sommerville, Sila Hopton, Angela Pyle, Michael Champion, Monika Ohlson, Triinu Siibak, Zofia M A Chrzanowska-Lightowlers, Robert W Taylor, Maria Falkenberg, Robert N Lightowlers
LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively-inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic...
March 6, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29516370/novel-mutation-of-ppox-gene-in-a-patient-with-abdominal-pain-and-syndrome-of-inappropriate-antidiuresis
#13
Isabella Tabaro, Giuseppe Reimondo, Giangiacomo Osella, Caterina Aurizi, Pasquale Caraci, Luca Barbieri, Daniela Francesca Giachino, Fabio Sirchia, Massimo Terzolo
PURPOSE: Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific. We report the case of a 40 year-old woman who presented many times to the emergency department complaining of unexplained abdominal pain and laboratory investigations showed repeatedly hyponatremia...
March 7, 2018: Endocrine
https://www.readbyqxmd.com/read/29479812/rare-lpl-gene-missense-mutation-in-an-infant-with-hypertriglyceridemia
#14
Yuan-Yuan Qin, Ai-Qiu Wei, Qing-Wen Shan, Xiao-Ying Xian, Yang-Yang Wu, Lin Liao, Jie Yan, Zhan-Feng Lai, Fa-Quan Lin
BACKGROUND: Severe hypertriglyceridemia usually results from a combination of genetic and environmental factors and is most often attributable to mutations in the lipoprotein lipase (LPL) gene. OBJECTIVES: The aim of this study was to identify rare mutations in the LPL gene causing severe hypertriglyceridemia. METHODS: A Chinese infant who presented classical features of severe hypertriglyceridemia recruited for DNA sequencing of the LPL gene...
February 25, 2018: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/29477724/loss-of-function-nfkb1-variants-are-the-most-common-monogenic-cause-of-cvid-in-europeans
#15
Paul Tuijnenburg, Hana Lango Allen, Siobhan O Burns, Daniel Greene, Machiel H Jansen, Emily Staples, Jonathan Stephens, Keren J Carss, Daniele Biasci, Helen Baxendale, Moira Thomas, Anita Chandra, Sorena Kiani-Alikhan, Hilary J Longhurst, Suranjith L Seneviratne, Eric Oksenhendler, Ilenia Simeoni, Godelieve J de Bree, Anton T J Tool, Ester M M van Leeuwen, Eduard H T M Ebberink, Alexander B Meijer, Salih Tuna, Deborah Whitehorn, Matthew Brown, Ernest Turro, Adrian J Thrasher, Kenneth G C Smith, James E Thaventhiran, Taco W Kuijpers
BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants...
February 22, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29444077/peculiar-combinations-of-individually-non-pathogenic-missense-mitochondrial-dna-variants-cause-low-penetrance-leber-s-hereditary-optic-neuropathy
#16
Leonardo Caporali, Luisa Iommarini, Chiara La Morgia, Anna Olivieri, Alessandro Achilli, Alessandra Maresca, Maria Lucia Valentino, Mariantonietta Capristo, Francesca Tagliavini, Valentina Del Dotto, Claudia Zanna, Rocco Liguori, Piero Barboni, Michele Carbonelli, Veronica Cocetta, Monica Montopoli, Andrea Martinuzzi, Giovanna Cenacchi, Giuseppe De Michele, Francesco Testa, Anna Nesti, Francesca Simonelli, Anna Maria Porcelli, Antonio Torroni, Valerio Carelli
We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model...
February 14, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29429572/mutations-in-the-baf-complex-subunit-dpf2-are-associated-with-coffin-siris-syndrome
#17
Georgia Vasileiou, Silvia Vergarajauregui, Sabine Endele, Bernt Popp, Christian Büttner, Arif B Ekici, Marion Gerard, Nuria C Bramswig, Beate Albrecht, Jill Clayton-Smith, Jenny Morton, Susan Tomkins, Karen Low, Astrid Weber, Maren Wenzel, Janine Altmüller, Yun Li, Bernd Wollnik, George Hoganson, Maria-Renée Plona, Megan T Cho, Christian T Thiel, Hermann-Josef Lüdecke, Tim M Strom, Eduardo Calpena, Andrew O M Wilkie, Dagmar Wieczorek, Felix B Engel, André Reis
Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2)...
February 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29401559/spectrum-of-mnx1-pathogenic-variants-and-associated-clinical-features-in-korean-patients-with-currarino-syndrome
#18
Seungjun Lee, Eun Jin Kim, Sung Im Cho, Hyunwoong Park, Soo Hyun Seo, Moon Woo Seong, Sung Sup Park, Sung Eun Jung, Seong Cheol Lee, Kwi Won Park, Hyun Young Kim
BACKGROUND: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS...
May 2018: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/29399970/analysis-of-dicer1-in-familial-and-sporadic-cases-of-transposition-of-the-great-arteries
#19
Nelly Sabbaghian, Maria C Digilio, Gillian M Blue, Timothée Revil, David S Winlaw, William D Foulkes
OBJECTIVE: We previously identified a pathogenic germline DICER1 variant in a child with transposition of the great arteries who was a member of a family with DICER1 syndrome. In view of a report linking Dicer1 knockout in murine cardiomyocytes to cardiac outflow defects, we investigated the involvement of DICER1 in transposition of the great arteries. DESIGN: We used Fluidigm access array followed by next generation sequencing to screen for variants in the coding exons, their exon/intron boundaries and the 3' untranslated region of DICER1 in patient DNA...
February 5, 2018: Congenital Heart Disease
https://www.readbyqxmd.com/read/29394989/assessment-of-the-clinical-relevance-of-brca2-missense-variants-by-functional-and-computational-approaches
#20
Lucia Guidugli, Hermela Shimelis, David L Masica, Vernon S Pankratz, Gary B Lipton, Namit Singh, Chunling Hu, Alvaro N A Monteiro, Noralane M Lindor, David E Goldgar, Rachel Karchin, Edwin S Iversen, Fergus J Couch
Many variants of uncertain significance (VUS) have been identified in BRCA2 through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. We conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had ≥99% probability of pathogenicity, and 73 had ≥95% probability of neutrality...
January 17, 2018: American Journal of Human Genetics
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