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

Area of Science:

• Genetics
• Molecular Biology
• Genomic Medicine

Background:

• Premature termination codons (PTCs) typically lead to transcript degradation via nonsense-mediated decay (NMD), resulting in loss-of-function (LoF).
• However, PTCs can escape NMD, producing truncated peptides that cause disease through gain-of-function (GoF) mechanisms.
• PTC location critically influences NMD escape and subsequent transcript fate.

Purpose of the Study:

• To hypothesize and test that depletion of protein-truncating variants (PTVs) in NMD-escape regions can rank genes for GoF versus LoF disease susceptibility.
• To develop and apply an NMD escape intolerance score for identifying candidate genes in Mendelian diseases.
• To provide a novel analytical tool for discovering genes associated with dominant traits via mechanisms other than LoF.

Main Methods:

• Developed an NMD escape intolerance score by analyzing PTV depletion in NMD-escape regions.
• Utilized Atherosclerosis Risk in Communities Study (ARIC) and Exome Aggregation Consortium (ExAC) control databases.
• Screened the Baylor-Center for Mendelian Genomics disease database to identify candidate genes.

Main Results:

• Identified 1,996 genes significantly depleted for PTVs predicted to escape NMD (PTVesc).
• A subset of these genes was validated as candidates for Mendelian phenotypes.
• Found that these candidate genes often possess low probability of LoF (pLI) scores, potentially masking them in dominant disease studies.

Conclusions:

• The NMD escape intolerance score is an effective tool for discovering genes involved in Mendelian diseases caused by truncated or altered proteins.
• This score aids in identifying genes associated with dominant traits through GoF mechanisms, complementing LoF-based approaches.
• The study highlights a distinct genetic mechanism for dominant diseases and provides a valuable tool for gene discovery.