Analysis of Premature Termination Codons Predicted to Escape Nonsense Mediated Decay Identifies Novel Genes, Pathways, and Networks Contributing to an Oligogenic Etiology of Congenital Heart Disease
Klonowski, J. F.; Ganapathiraju, M.; Rai, A.; Glennon, B.; Coban-Akdemir, Z.; Kostka, D.; Lo, C.
Show abstract
BackgroundA large fraction of clinically relevant pathogenic genomic variation consists of premature termination codons (PTC). While PTCs can trigger nonsense mediated mRNA decay (NMDtrig) causing loss of function (LOF), those near the end of transcripts can escape NMD (NMDesc), allowing expression of truncated proteins. As NMDesc PTCs are not well studied, and can lead to possible gain of function (GOF) effects, we investigated the impact of NMDtrig/NMDesc PTCs on human congenital heart disease (CHD). ResultsWhole exome sequencing data from [~]3,000 CHD patients and [~]5,000 control subjects were analyzed for PTCs using known rules for classifying variants as NMDtrig/NMDesc. CHD patients had an increased burden of PTCs in gene-sets related to both heart and brain developmental processes. NMDesc PTCs were enriched in the MAPK pathway, known to harbor GOF variants that cause Noonan syndrome. Also identified were Hedgehog and ERBB signaling, pathways with prominent roles in heart development but not previously reported in nonsyndromic CHD. NMD analysis of PTCs at the transcript level identified 11 genes (9 novel) associated with CHD. Enrichment of digenic combinations between these 11 genes and digenic and higher order combinations of PTCs within heart developmental genes suggest a role for oligogenicity. ConclusionsWe observed NMDesc PTCs play a role in CHD pathogenesis, and this role may be disproportionately specific to heart development. Our analysis uncovered new genes and pathways, identifying MAPK, Hedgehog, and ERBB signaling as pathways contributing to nonsyndromic CHD. The additional observation of digenic and higher order combinations of PTCs suggests an oligogenic framework to the genetic architecture of human CHD.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot 96%
- Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population 93%
- Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant 93%
Similar papers in this journal
Similar papers in this journal
- Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach 97%
- Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects 92%
- Mutations in MYLPF cause a novel segmental amyoplasia that manifests as distal arthrogryposis 91%
Similar papers in this journal
- Performance of a Protein Language Model for Variant Annotation in Cardiac Disease 94%
- The effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death 93%
- Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.