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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A novel nonsense mutation in TNNT2 in a Chinese pedigree with hypertrophic cardiomyopathy: A case report
Guangyuan Gao,Guohui Liu,Weiwei Chen,Yaliang Tong,Cuiying Mao,Jinsha Liu,Xing Zhang,Max M He,Ping Yang +8 more
TL;DR: Since HCM shows a low penetrance by clinical criteria in adolescents, the adolescent mutation carrier, who is still clinically unaffected, should be offered routine follow-ups and sport activity recommendations to prevent adverse events including sudden cardiac death in the future.
Patent
Drug Sensitivity related Gene Expression and Copy Number Variation based Functional Haplotyping Methods and System
TL;DR: In this paper, a new learning model was proposed to predict responsiveness of a drug by coupling analysis of a molecular profile of the drug after transforming specific genetic variation fingerprints related to diseases including a cancer into a haplotype having functional information.
Journal ArticleDOI
Predictive significance of selected gene mutations in relapsed and refractory chronic lymphocytic leukemia patients treated with ibrutinib
Marcin M Machnicki,Patryk Górniak,Monika Pepek,Agnieszka Szymczyk,Elżbieta Iskierka-Jażdżewska,Paweł Steckiewicz,Aleksandra Bluszcz,Małgorzata Rydzanicz,Marek Hus,Rafał Płoski,Hanna Makuch-Łasica,Grazyna Nowak,Przemyslaw Juszczynski,Krzysztof Jamroziak,Tomasz Stoklosa,Bartosz Pula +15 more
TL;DR: Ibrutinib, an inhibitor of the Bruton's kinase (BTK), is characterized by high efficacy in the therapy of patients with relapsed and refractory chronic lymphocytic leukemia (RR‐CLL).
Journal ArticleDOI
Adrenal Medullary Hyperplasia, An Under the Radar Cause of Endocrine Hypertension.
TL;DR: The case of a 48-year-old Hispanic woman who presented for evaluation of resistant hypertension with several episodes of hypertensive crisis, and the pathology study revealed the presence of adrenal medullary hyperplasia.
Journal ArticleDOI
Kabuki Syndrome: Identification of Two Novel Variants in KMT2D and KDM6A.
Mehrnoosh Khodaeian,Ehsan Jafarinia,Fatemeh Bitarafan,Shohreh Shafeii,Navid Almadani,Mohammad Ali Daneshmand,Masoud Garshasbi +6 more
TL;DR: In this article, the potential effects of frameshift variants on the structure and function of respective proteins were tested using in silico predictions, which provided evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.
References
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