Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
Hashem A. Shihab,Julian Gough,David Neil Cooper,Peter D. Stenson,Gary L A Barker,Keith J. Edwards,Ian N. M. Day,Tom R. Gaunt +7 more
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TLDR
The Functional Analysis Through Hidden Markov Models (FATHMM) software and server is described: a species‐independent method with optional species‐specific weightings for the prediction of the functional effects of protein missense variants, demonstrating that FATHMM can be efficiently applied to high‐throughput/large‐scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations.Abstract:
The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk.read more
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Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.
Leticia De Mattos-Arruda,Leticia De Mattos-Arruda,Leticia De Mattos-Arruda,Charlotte K.Y. Ng,Charlotte K.Y. Ng,Charlotte K.Y. Ng,Salvatore Piscuoglio,Salvatore Piscuoglio,Maria Gonzalez-Cao,Raymond S. Lim,Maria R. De Filippo,Nicola Fusco,Anne M. Schultheis,Carolina Ortiz,Santiago Viteri,Alexandra Arias,Gabriel S Macedo,Mafalda Oliveira,Patricia Gomez,Cristina Teixidó,Paolo Nuciforo,Vicente Peg,Cristina Saura,Santiago Ramón y Cajal,Francesc Tresserra Casas,Britta Weigelt,Javier Cortes,Javier Cortes,Joan Seoane,Joan Seoane,Joan Seoane,Jorge S. Reis-Filho +31 more
TL;DR: The repertoire of mutations private to or enriched for in HER2-positive brain metastases is defined, with potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.
Journal ArticleDOI
Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy
Takeharu Hayashi,Takeharu Hayashi,Kousuke Tanimoto,Kayoko Hirayama-Yamada,Etsuko Tsuda,Mamoru Ayusawa,Shinichi Nunoda,Akira Hosaki,Akinori Kimura +8 more
TL;DR: In this study, pediatric HCM and RCM patients were found to carry disease-associated genetic variants at a high rate, most of the variants were in MYH7 or MYPBC3 for H CM and TNNT2 or TNNI3 for RCM.
Journal ArticleDOI
HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes
Sasha Howard,Roberto Oleari,Ariel Poliandri,Vasiliki Chantzara,Alessandro Fantin,Gerard Ruiz-Babot,Louise A. Metherell,Claudia P. Cabrera,Michael R. Barnes,Karoliina Wehkalampi,Leonardo Guasti,Christiana Ruhrberg,Anna Cariboni,Anna Cariboni,Leo Dunkel +14 more
TL;DR: It is shown that heterozygous Hs6st1 loss causes DP in mice and the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.
Journal ArticleDOI
How to Identify Pathogenic Mutations among All Those Variations: Variant Annotation and Filtration in the Genome Sequencing Era
David Salgado,Matthew I. Bellgard,Matthew I. Bellgard,Jean-Pierre Desvignes,Christophe Béroud +4 more
TL;DR: The critical steps of variant annotation and filtration processes to highlight a handful of potential disease‐causing mutations for downstream analysis are described and the key annotation elements to gather at multiple levels for each mutation are reported.
Journal ArticleDOI
Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.
Hugo Larose,Nina Prokoph,Jamie D. Matthews,Michaela Schlederer,Sandra Högler,Ali F. Alsulami,Stephen P. Ducray,Edem Nuglozeh,Feroze Fazaludeen,Ahmed Elmouna,Monica Ceccon,Luca Mologni,Carlo Gambacorti-Passerini,Gerald Hoefler,Cosimo Lobello,Šárka Pospíšilová,Andrea Janíková,Wilhelm Woessmann,Christine Damm-Welk,Martin Zimmermann,Alina Federova,Andrea Malone,Owen P. Smith,Mariusz A. Wasik,Giorgio Inghirami,Laurence Lamant,Tom L. Blundell,Wolfram Klapper,Olaf Merkel,G. A. Amos Burke,Shahid Mian,Ibraheem Ashankyty,Lukas Kenner,Suzanne D. Turner +33 more
TL;DR: A variant in the extracellular domain of NOTCH1 is shown that provides a growth advantage to cells and the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL is confirmed.
References
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