Prospective functional classification of all possible missense variants in PPARG.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620058
Title:
Prospective functional classification of all possible missense variants in PPARG.
Authors:
Majithia, A R; Tsuda, B.; Agostini, M.; Gnanapradeepan, K.; Rice, R.; Peloso, G.; Patel, K. A.; Zhang, X.; Broekema, M. F.; Patterson, N.; Duby, M.; Sharpe, T.; Kalkhoven, E.; Rosen, E. D.; Barroso, I.; Ellard, Sian ( 0000-0002-7620-5526 ) ; Kathiresan, S.; O'Rahilly, S.; Chatterjee, K.; Florez, J. C.; Mikkelsen, T.; Savage, D. B.; Altshuler, D.
Abstract:
Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.
Citation:
Prospective functional classification of all possible missense variants in PPARG. 2016 Dec;48(12):1570-1575 Nat. Genet.
Publisher:
Nature
Journal:
Nature Genetics
Issue Date:
17-Oct-2016
URI:
http://hdl.handle.net/11287/620058
DOI:
10.1038/ng.3700
PubMed ID:
27749844
Additional Links:
http://dx.doi.org/10.1038/ng.3700
Type:
Journal Article
Language:
en
ISSN:
1546-1718
Appears in Collections:
Molecular Genetics; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMajithia, A Ren
dc.contributor.authorTsuda, B.en
dc.contributor.authorAgostini, M.en
dc.contributor.authorGnanapradeepan, K.en
dc.contributor.authorRice, R.en
dc.contributor.authorPeloso, G.en
dc.contributor.authorPatel, K. A.en
dc.contributor.authorZhang, X.en
dc.contributor.authorBroekema, M. F.en
dc.contributor.authorPatterson, N.en
dc.contributor.authorDuby, M.en
dc.contributor.authorSharpe, T.en
dc.contributor.authorKalkhoven, E.en
dc.contributor.authorRosen, E. D.en
dc.contributor.authorBarroso, I.en
dc.contributor.authorEllard, Sianen
dc.contributor.authorKathiresan, S.en
dc.contributor.authorO'Rahilly, S.en
dc.contributor.authorChatterjee, K.en
dc.contributor.authorFlorez, J. C.en
dc.contributor.authorMikkelsen, T.en
dc.contributor.authorSavage, D. B.en
dc.contributor.authorAltshuler, D.en
dc.date.accessioned2016-10-28T13:53:53Z-
dc.date.available2016-10-28T13:53:53Z-
dc.date.issued2016-10-17-
dc.identifier.citationProspective functional classification of all possible missense variants in PPARG. 2016 Dec;48(12):1570-1575 Nat. Genet.en
dc.identifier.issn1546-1718-
dc.identifier.pmid27749844-
dc.identifier.doi10.1038/ng.3700-
dc.identifier.urihttp://hdl.handle.net/11287/620058-
dc.description.abstractClinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.en
dc.languageENG-
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/ng.3700en
dc.rightsArchived with thanks to Nature geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleProspective functional classification of all possible missense variants in PPARG.en
dc.typeJournal Articleen
dc.identifier.journalNature Geneticsen
dc.type.versionIn press (epub ahead of print)en

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