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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Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1
Hande Kocak,Bari J. Ballew,Kamlesh Bisht,Rebecca Eggebeen,Belynda Hicks,Shalabh Suman,Adri O’Neil,Neelam Giri,Ivan Maillard,Blanche P. Alter,Catherine E. Keegan,Jayakrishnan Nandakumar,Sharon A. Savage +12 more
TL;DR: Exome sequencing identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by Hoyeraal-Hreidarsson syndrome, demonstrating that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.
Journal ArticleDOI
The Genomic Landscape of Male Breast Cancers
Salvatore Piscuoglio,Charlotte K.Y. Ng,Melissa Murray,Elena Guerini-Rocco,Luciano G. Martelotto,Felipe C Geyer,François-Clément Bidard,Samuel H. Berman,Nicola Fusco,Rita A. Sakr,Carey A. Eberle,Leticia De Mattos-Arruda,Gabriel S Macedo,Muzaffar Akram,Timour Baslan,James W. Hicks,Tari A. King,Edi Brogi,Larry Norton,Britta Weigelt,Clifford A. Hudis,Jorge S. Reis-Filho +21 more
TL;DR: Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes.
Journal ArticleDOI
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus
Charuta G. Furey,Jungmin Choi,Sheng Chih Jin,Xue Zeng,Andrew T. Timberlake,Carol Nelson-Williams,M. Shahid Mansuri,Qiongshi Lu,Daniel Duran,Shreyas Panchagnula,August A Allocco,Jason K. Karimy,Arjun Khanna,Jonathan Gaillard,Tyrone DeSpenza,Prince Antwi,Erin Loring,William E. Butler,Edward R. Smith,Benjamin C. Warf,Jennifer Strahle,David D. Limbrick,Phillip B. Storm,Phillip B. Storm,Gregory G. Heuer,Gregory G. Heuer,Eric M. Jackson,Bermans J. Iskandar,James M. Johnston,Irina Tikhonova,Christopher Castaldi,Francesc López-Giráldez,Robert D. Bjornson,James R. Knight,Kaya Bilguvar,Shrikant M. Mane,Seth L. Alper,Shozeb Haider,Bulent Guclu,Yasar Bayri,Yener Sahin,Michael L.J. Apuzzo,Charles C. Duncan,Michael L. DiLuna,Murat Gunel,Richard P. Lifton,Richard P. Lifton,Kristopher T. Kahle +47 more
TL;DR: Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations and four genes required for neural tube development and regulate ventricular zone neural stem cell fate, implicate impaired neurogenesis in the pathogenesis of a subset of CH patients.
Journal ArticleDOI
Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression
Salvatore Piscuoglio,Charlotte K.Y. Ng,Melissa Murray,Kathleen A. Burke,Marcia Edelweiss,Felipe C Geyer,Gabriel S Macedo,Akiko Inagaki,Anastasios D. Papanastasiou,Luciano G. Martelotto,Caterina Marchiò,Caterina Marchiò,Raymond S. Lim,Rafael A. Ioris,Pooja K. Nahar,Ino de Bruijn,Lillian M. Smyth,Muzaffar Akram,Dara S. Ross,John H.J. Petrini,Larry Norton,David B. Solit,José Baselga,Edi Brogi,Marc Ladanyi,Britta Weigelt,Jorge S. Reis-Filho +26 more
TL;DR: It is suggested that TERT alterations may drive the progression of PTs, and may assist in the differential diagnosis between PTs and fibroadenomas.
Journal ArticleDOI
An optimized prediction framework to assess the functional impact of pharmacogenetic variants.
TL;DR: This novel model holds promise to improve the translation of personal genetic information into biological conclusions and pharmacogenetic recommendations, thereby facilitating the implementation of Next-Generation Sequencing data into clinical diagnostics.
References
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