Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles

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dc.contributor.authorCoban-Akdemir, Zeynep
dc.contributor.authorWhite, Janson J.
dc.contributor.authorSong, Xiaofei
dc.contributor.authorJhangiani, Shalini N.
dc.contributor.authorFatih, Jawid M.
dc.contributor.authorGambin, Tomasz
dc.contributor.authorBayram, Yavuz
dc.contributor.authorChinn, Ivan K.
dc.contributor.authorKaraca, Ender
dc.contributor.authorPunetha, Jaya
dc.contributor.authorPoli, Cecilia
dc.contributor.authorBaylor-Hopkins Center for Mendelian Genomics
dc.contributor.authorBoerwinkle, Eric
dc.contributor.authorShaw, Chad A.
dc.contributor.authorOrange, Jordan S.
dc.contributor.authorGibbs, Richard A.
dc.contributor.authorLappalainen, Tuuli
dc.contributor.authorLupski, James R.
dc.contributor.authorCarvalho, Claudia M.B.
dc.date.accessioned2022-05-28T00:15:39Z
dc.date.available2022-05-28T00:15:39Z
dc.date.issued2018
dc.description.abstractPremature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.es
dc.description.versionVersión Publicadaes
dc.identifier.citationCoban-Akdemir Z, White JJ, Song X, Jhangiani SN, Fatih JM, Gambin T, Bayram Y, Chinn IK, Karaca E, Punetha J, Poli C; Baylor-Hopkins Center for Mendelian Genomics, Boerwinkle E, Shaw CA, Orange JS, Gibbs RA, Lappalainen T, Lupski JR, Carvalho CMB. Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles. Am J Hum Genet. 2018 Aug 2;103(2):171-187. doi: 10.1016/j.ajhg.2018.06.009.es
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2018.06.009es
dc.identifier.urihttp://hdl.handle.net/11447/6155
dc.language.isoenes
dc.subjectNMD escape intolerance scoreses
dc.subjectNMDEscPredictores
dc.subjectWES analysises
dc.subjectAntimorphices
dc.subjectBioinformatic tooles
dc.subjectDominant negativees
dc.subjectFrameshift alleleses
dc.subjectGenotype-phenotype correlationses
dc.subjectNonsense-mediated decayes
dc.subjectStopgain variantses
dc.titleIdentifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleleses
dc.typeArticlees
dcterms.sourceThe American Journal of Human Geneticses

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