ArticleAmerican journal of human genetics2018
Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers, 2 of them syntheses that pooled it.
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Who cites it
149 citing papers in PubMed, 2 syntheses or guidelines pooled it, 230 citations in OpenAlex.
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- Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.Genome medicine · 2022Pooled it
- IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.Human genetics · 2021Trial
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- A homozygous frameshift variant in the CILK1 gene causes cranioectodermal dysplasia.European journal of human genetics : EJHG · 2025Article
- C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Clinical and Allelic Heterogeneity in a Small Cohort of Patients with Inherited Epidermolysis Bullosa.International journal of molecular sciences · 2025Article
89 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 4 institutions in 3 countries.
Funding
Abstract
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.
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