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Missense variants & pathogenicity prediction

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https://www.readbyqxmd.com/read/29224215/deleterious-variants-in-dchs1-are-prevalent-in-sporadic-cases-of-mitral-valve-prolapse
#1
Alisson Clemenceau, Jean-Christophe Bérubé, Paméla Bélanger, Nathalie Gaudreault, Maxime Lamontagne, Oumhani Toubal, Marie-Annick Clavel, Romain Capoulade, Patrick Mathieu, Philippe Pibarot, Yohan Bosse
BACKGROUND: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. METHODS: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico...
December 10, 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29208948/a-novel-mutation-in-slc1a3-causes-episodic-ataxia
#2
Kazuhiro Iwama, Aya Iwata, Masaaki Shiina, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kazuhiro Ogata, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto
Episodic ataxias (EAs) are rare channelopathies characterized by recurrent ataxia and vertigo, having eight subtypes. Mutated genes were found in four of these eight subtypes (EA1, EA2, EA5, and EA6). To date, only four missense mutations in the Solute Carrier Family 1 Member 3 gene (SLC1A3) have been reported to cause EA6. SLC1A3 encodes excitatory amino-acid transporter 1, which is a trimeric transmembrane protein responsible for glutamate transport in the synaptic cleft. In this study, we found a novel missense mutation, c...
December 5, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29197658/utilizing-the-genome-aggregation-database-computational-pathogenicity-prediction-tools-and-patch-clamp-heterologous-expression-studies-to-demote-previously-published-type-1-long-qt-syndrome-mutations-from-pathogenic-to-benign
#3
Daniel J Clemens, Anne R Lentino, Jamie D Kapplinger, Dan Ye, Wei Zhou, David J Tester, Michael J Ackerman
BACKGROUND: Mutations in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). It has been suggested that ∼10-20% of rare LQTS case-derived variants in the literature may have been published erroneously as LQT1-causative mutations and may be "false positives." OBJECTIVE: To determine which previously published KCNQ1 case variants are likely false positives. METHODS: A list of all published, case-derived KCNQ1 missense variants (MVs) was compiled...
November 29, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29196973/a-novel-homozygous-mutation-in-sptbn2-leads-to-spinocerebellar-ataxia-in-a-consanguineous-family-report-of-a-new-infantile-onset-case-and-brief-review-of-the-literature
#4
Mohammad A Al-Muhaizea, Faten AlMutairi, Rawan Almass, Safinaz AlHarthi, Mazhor S Aldosary, Maysoon Alsagob, Ali AlOdaib, Dilek Colak, Namik Kaya
The objective of this study was the identification of likely genes and mutations associated with an autosomal recessive (AR) rare spinocerebellar ataxia (SCA) phenotype in two patients with infantile onset, from a consanguineous family. Using genome-wide SNP screening, autozygosity mapping, targeted Sanger sequencing and nextgen sequencing, family segregation analysis, and comprehensive neuropanel, we discovered a novel mutation in SPTBN2. Next, we utilized multiple sequence alignment of amino acids from various species as well as crystal structures provided by protein data bank (PDB# 1WYQ and 1WJM) to model the mutation site and its effect on β-III-spectrin...
December 1, 2017: Cerebellum
https://www.readbyqxmd.com/read/29179779/evaluation-of-in-silico-algorithms-for-use-with-acmg-amp-clinical-variant-interpretation-guidelines
#5
Rajarshi Ghosh, Ninad Oak, Sharon E Plon
BACKGROUND: The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants...
November 28, 2017: Genome Biology
https://www.readbyqxmd.com/read/29178643/role-of-wnt10a-in-failure-of-tooth-development-in-humans-and-zebrafish
#6
Qiuping Yuan, Min Zhao, Bhavna Tandon, Lorena Maili, Xiaoming Liu, Anqi Zhang, Evan H Baugh, Tam Tran, Renato M Silva, Jacqueline T Hecht, Eric C Swindell, Daniel S Wagner, Ariadne Letra
BACKGROUND: Oligodontia is a severe form of tooth agenesis characterized by the absence of six or more permanent teeth. Oligodontia has complex etiology and variations in numerous genes have been suggested as causal for the condition. METHODS: We applied whole-exome sequencing (WES) to identify the cause of oligodontia in a 9-year-old girl missing 11 permanent teeth. Protein modeling and functional analysis in zebrafish were also performed to understand the impact of identified variants on the phenotype...
November 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29170251/clustered-f8-missense-mutations-cause-hemophilia-a-by-combined-alteration-of-splicing-and-protein-biosynthesis-activity
#7
Irving Donadon, John H McVey, Isabella Garagiola, Alessio Branchini, Mimosa Mortarino, Flora Peyvandi, Francesco Bernardi, Mirko Pinotti
Dissection of pleiotropic effects of missense mutations, scarcely investigated in inherited diseases, is fundamental to understanding genotype-phenotype relationships. Missense mutations might impair mRNA processing in addition to protein properties. As a model for haemophilia A (HA) we investigated the highly prevalent F8 p.R2016W/c.6046c>t (exon 19) mutation. In expression studies exploiting lentiviral vectors, we demonstrated that the aminoacid change impairs both secretion (FVIII:Ag 11.0+/-0.4% of wild-type) and activity (FVIII:C 6...
November 23, 2017: Haematologica
https://www.readbyqxmd.com/read/29161432/modeling-mutant-wild-type-interactions-to-ascertain-pathogenicity-of-prokr2-missense-variants-in-patients-with-isolated-gnrh-deficiency
#8
Kimberly H Cox, Luciana M B Oliveira, Lacey Plummer, Braden Corbin, Thomas Gardella, Ravikumar Balasubramanian, William F Crowley
A major challenge in human genetics is the validation of pathogenicity of heterozygous missense variants. This problem is well-illustrated by PROKR2 variants associated with Isolated GnRH Deficiency (IGD). Homozygous, loss of function variants in PROKR2 were initially implicated in autosomal recessive IGD; however, most IGD-associated PROKR2 variants are heterozygous. Moreover, while IGD patient cohorts are enriched for PROKR2 missense variants similar rare variants are also found in normal individuals. To elucidate the pathogenic mechanisms distinguishing IGD-associated PROKR2 variants from rare variants in controls, we assessed 59 variants using three approaches: (i) in silico prediction, (ii) traditional in vitro functional assays across 3 signaling pathways with mutant-alone transfections, and (iii) modified in vitro assays with mutant and wild-type expression constructs co-transfected to model in vivo heterozygosity...
November 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29159838/eys-mutation-update-in-silico-assessment-of-271-reported-and-26-novel-variants-in-patients-with-retinitis-pigmentosa
#9
Muriël Messchaert, Lonneke Haer-Wigman, Muhammad I Khan, Frans P M Cremers, Rob W J Collin
Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www...
November 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/29154924/characterization-of-three-novel-pathogenic-slc40a1-mutations-and-genotype-phenotype-correlations-in-7-italian-families-with-type-4-hereditary-hemochromatosis
#10
Silvia Majore, Maria Carmela Bonaccorsi di Patti, Michele Valiante, Fabio Polticelli, Andrea Cortese, Sabrina Di Bartolomeo, Carmelilia De Bernardo, Marianna De Muro, Fiorella Faienza, Francesca Clementina Radio, Paola Grammatico, Giovanni Musci
Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron exporter, severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations. This disease can be classified as type 4A, better known as "ferroportin disease", which is due to "loss of function" mutations that lead to decreased iron export from cells, or as type 4B hemochromatosis, which is caused by "gain of function" mutations, conferring partial or complete resistance to hepcidin-mediated Fpn degradation...
November 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29152850/estimation-of-minimal-disease-prevalence-from-population-genomic-data-application-to-primary-familial-brain-calcification
#11
Gaël Nicolas, Camille Charbonnier, Dominique Campion, Joris A Veltman
Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance...
November 20, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/29098742/a-comprehensive-approach-to-identification-of-pathogenic-fanca-variants-in-fanconi-anemia-patients-and-their-families
#12
Danielle C Kimble, Francis P Lach, Siobhan Q Gregg, Frank X Donovan, Elizabeth K Flynn, Aparna Kamat, Alice Young, Meghana Vemulapalli, James W Thomas, James C Mullikin, Arleen D Auerbach, Agata Smogorzewska, Settara C Chandrasekharappa
Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity...
November 2, 2017: Human Mutation
https://www.readbyqxmd.com/read/29077808/titindb-a-computational-tool-to-assess-titin-s-role-as-a-disease-gene
#13
Anna Laddach, Mathias Gautel, Franca Fraternali
Summary: Large numbers of rare and unique titin missense variants have been discovered in both healthy and disease cohorts, thus the correct classification of variants as pathogenic or non-pathogenic has become imperative. Due to titin's large size (363 coding exons), current web applications are unable to map titin variants to domain structures. Here, we present a web application, TITINdb, which integrates titin structure, variant, sequence and isoform information, along with pre-computed predictions of the impact of non-synonymous single nucleotide variants, to facilitate the correct classification of titin variants...
November 1, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29069390/crimetoyhu-a-new-web-tool-to-develop-yeast-based-functional-assays-for-characterizing-cancer-associated-missense-variants
#14
Alberto Mercatanti, Samuele Lodovichi, Tiziana Cervelli, Alvaro Galli
Evaluation of functional impact of cancer-associated missense variants is more difficult to assess as compared to protein-truncating mutations and, consequently, standard guidelines for the interpretation of sequence variants have been recently proposed. A number of algorithms and software products were developed to predict the impact of cancer-associated missense mutations on protein structure and function. Importantly, direct assessment of the variants using high-throughput functional assays using simple genetic systems can help in speeding up the functional evaluation of newly identified cancer associated variants...
October 23, 2017: FEMS Yeast Research
https://www.readbyqxmd.com/read/29034544/cyp2u1-activity-is-altered-by-missense-mutations-in-hereditary-spastic-paraplegia-56
#15
Christelle M Durand, Laura Dhers, Christelle Tesson, Alessandra Tessa, Laetitia Fouillen, Stéphanie Jacqueré, Laure Raymond, Isabelle Coupry, Giovanni Benard, Frédéric Darios, Khalid H El-Hachimi, Guja Astrea, François Rivier, Guillaume Banneau, Claire Pujol, Didier Lacombe, Alexandra Durr, Patrick J Babin, Filippo M Santorelli, Nicolas Pietrancosta, Jean-Luc Boucher, Daniel Mansuy, Giovanni Stevanin, Cyril Goizet
Hereditary Spastic Paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying 3 novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/29028823/novel-mutations-in-darier-disease-and-association-to-self-reported-disease-severity
#16
Ivone U S Leong, Alexander Stuckey, Tara Ahanian, Martin Cederlöf, Jakob D Wikstrom
Darier disease is a rare and severe autosomal dominant skin disease characterised by malodorous keratotic papules in seborrheic areas of the skin. Darier disease affects up to 1 in 30 000 people and is caused by mutations in the ATP2A2 gene, which encodes to the sarco/endoplasmic reticulum calcium-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum. Although many ATP2A2 variants have been described, it is not known if genotype correlates with phenotype, which could be important for prognosis and treatment...
2017: PloS One
https://www.readbyqxmd.com/read/28965847/hypomorphic-recessive-variants-in-sufu-impair-the-sonic-hedgehog-pathway-and-cause-joubert-syndrome-with-cranio-facial-and-skeletal-defects
#17
Roberta De Mori, Marta Romani, Stefano D'Arrigo, Maha S Zaki, Elisa Lorefice, Silvia Tardivo, Tommaso Biagini, Valentina Stanley, Damir Musaev, Joel Fluss, Alessia Micalizzi, Sara Nuovo, Barbara Illi, Luisa Chiapparini, Lucia Di Marcotullio, Mahmoud Y Issa, Danila Anello, Antonella Casella, Monia Ginevrino, Autumn Sa'na Leggins, Susanne Roosing, Romina Alfonsi, Jessica Rosati, Rachel Schot, Grazia Maria Simonetta Mancini, Enrico Bertini, William B Dobyns, Tommaso Mazza, Joseph G Gleeson, Enza Maria Valente
The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28965491/compound-heterozygous-mutations-in-uba5-causing-early-onset-epileptic-encephalopathy-in-two-sisters
#18
Gudny A Arnadottir, Brynjar O Jensson, Sigurdur E Marelsson, Gerald Sulem, Asmundur Oddsson, Ragnar P Kristjansson, Stefania Benonisdottir, Sigurjon A Gudjonsson, Gisli Masson, Gudmundur A Thorisson, Jona Saemundsdottir, Olafur Th Magnusson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Reynir Arngrimsson, Patrick Sulem, Kari Stefansson
BACKGROUND: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease...
October 2, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28965043/a-novel-pax9-mutation-causing-oligodontia
#19
Eiman Mohammed Daw, Christian Saliba, Godfrey Grech, Simon Camilleri
INTRODUCTION: An extended family presenting with several members affected by developmentally missing teeth was investigated by analysis of the MSX1 and PAX9 genes. MATERIALS AND METHODS: Saliva samples were collected and DNA extracted. Primers were designed to span the exons and intron-exon junctions of the MSX1 and PAX9 genes. These primers were optimised using gradient Polymerase Chain Reaction. The amplified fragments were sent for Sanger sequencing RESULTS: a novel heterozygote missense mutation in exon 3 of PAX9 (c...
September 25, 2017: Archives of Oral Biology
https://www.readbyqxmd.com/read/28950846/analysis-of-the-vsx1-gene-in-sporadic-keratoconus-patients-from-china
#20
Tao Guan, Xue Wang, Li-Bin Zheng, Hai-Jian Wu, Yu-Feng Yao
BACKGROUND: Keratoconus normally presents as a sporadic disease. Although different studies have found sequence variants of the visual system homeobox 1 (VSX1) gene associated with keratoconus in humans, no research has detected such variants in sporadic keratoconus patients from China. To investigate the possibility of VSX1 being a candidate susceptibility gene for Chinese patients with sporadic keratoconus, we performed sequence screening of this gene in such patients. METHODS: Whole DNA was obtained from the leukocytes in the peripheral venous blood of 50 patients with sporadic keratoconus and 50 control subjects without this ocular disorder...
September 26, 2017: BMC Ophthalmology
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