TY - JOUR
T1 - Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles
AU - Baylor-Hopkins Center for Mendelian Genomics
AU - Coban-Akdemir, Zeynep
AU - White, Janson J.
AU - Song, Xiaofei
AU - Jhangiani, Shalini N.
AU - Fatih, Jawid M.
AU - Gambin, Tomasz
AU - Bayram, Yavuz
AU - Chinn, Ivan K.
AU - Karaca, Ender
AU - Punetha, Jaya
AU - Poli, Cecilia
AU - Boerwinkle, Eric
AU - Shaw, Chad A.
AU - Orange, Jordan S.
AU - Gibbs, Richard A.
AU - Lappalainen, Tuuli
AU - Lupski, James R.
AU - Carvalho, Claudia M.B.
N1 - Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/8/2
Y1 - 2018/8/2
N2 - Premature 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.
AB - Premature 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.
KW - NMD escape intolerance scores
KW - NMDEscPredictor
KW - WES analysis
KW - antimorphic
KW - bioinformatic tool
KW - dominant negative
KW - frameshift alleles
KW - genotype-phenotype correlations
KW - nonsense-mediated decay
KW - stopgain variants
UR - http://www.scopus.com/inward/record.url?scp=85050690468&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.06.009
DO - 10.1016/j.ajhg.2018.06.009
M3 - Article
C2 - 30032986
AN - SCOPUS:85050690468
SN - 0002-9297
VL - 103
SP - 171
EP - 187
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -