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Am J Hum Genet. 2018 Aug 2;103(2):171-187. doi: 10.1016/j.ajhg.2018.06.009. Epub 2018 Jul 19.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Institute of Computer Science, Warsaw University of Technology, Warsaw 00-665, Poland.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy and Rheumatology, Houston, TX 77030, USA.
6
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy and Rheumatology, Houston, TX 77030, USA; Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clinica Alemana de Santiago, Santiago RM7590943, Chile.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
10
New York Genome Center, New York, NY 10013, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
11
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: cfonseca@bcm.edu.

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.

KEYWORDS:

NMD escape intolerance scores; NMDEscPredictor; WES analysis; antimorphic; bioinformatic tool; dominant negative; frameshift alleles; genotype-phenotype correlations; nonsense-mediated decay; stopgain variants

PMID:
30032986
PMCID:
PMC6081281
DOI:
10.1016/j.ajhg.2018.06.009
[Indexed for MEDLINE]
Free PMC Article

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