ArticleAmerican journal of human genetics2024
Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.
Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 30 citations in OpenAlex.
- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms.American journal of human genetics · 2026Article
- The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region.Life science alliance · 2026Article
- Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders.Human genomics · 2026Article
- RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.Annals of clinical and translational neurology · 2026Article
- Regional nonsense constraint offers biological and clinical insights into genetic disease.Nature communications · 2026Article
- Phenotypic expansion of CALM1/2-associated disorders to include neurologic phenotypes without arrhythmia.Human molecular genetics · 2026Article
- Opportunities for RNA sequencing in physiology: from big data to understanding homeostasis and heterogeneity.Function (Oxford, England) · 2026Review
- Nonsense-mediated mRNA decay and associated splicing patterns in neurodevelopmental disorders.Frontiers in molecular biosciences · 2026Review
- Cellular Functional Analyses ofHuman mutation · 2026Article
- Analysis and Interpretation of Somatic NMD-Escaping Variants in Oncogenes and Dual-Function Genes across Adult and Pediatric Cancer Cohorts.medRxiv : the preprint server for health sciences · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Dilated cardiomyopathy in patients with PRDM16 haploinsufficiency.Journal of molecular medicine (Berlin, Germany) · 2025Article
- SpliPath enhances disease gene discovery in case-control analyses of rare splice-altering genetic variants.Cell reports methods · 2025Article
- A homozygous frameshift variant in the CILK1 gene causes cranioectodermal dysplasia.European journal of human genetics : EJHG · 2025Article
- Nonsense-Mediated mRNA Decay in Human Health and Diseases: Current Understanding, Regulatory Mechanisms and Future Perspectives.Molecular biotechnology · 2025Review
- GDC: Integration of Multi-Omic and Phenotypic Resources to Unravel the Genetic Pathogenesis of Hearing Loss.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Molecular characterization of imprinting disorders: Beckwith-Wiedemann, Silver-Russell, and Prader-Willi syndromes in Egyptian patients.BMC pediatrics · 2025Article
- Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing.NPJ genomic medicine · 2025Article
- Identification and functional analysis of a novel TBC1D23 pathogenic variant in a Chinese family with pontocerebellar hypoplasia.Human genomics · 2025Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.
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