{"doi":"10.64898/2025.12.01.25341387","title":"Phase Separation Contributes to Pathogenicity for Nonsense Mediated Decay-Escaping Variant Alleles","abstract":"ABSTRACT Nonsense-mediated decay (NMD) as an RNA-surveillance pathway degrades transcripts with variants introducing premature termination codons (i.e., PTC-variants), yet a substantial subset of pathogenic PTC-variants downstream of the final exon–exon junction is predicted to escape NMD (NMD-escape) based on the canonical 50-bp rule. Our systematic analysis of germline pathogenic PTC-variants from ClinVar revealed 148 autosomal dominant (AD) disease genes enriched for predicted NMD-escape alleles. These genes span nonsense (N=63), −1 frameshift (N=34), and +1 frameshift (N=22) variants, with 23 genes enriched for two classes and 6 for all three. Although their loss-of-function intolerance score distributions did not differ from controls (P = 0.407), these genes exhibited significantly higher protein–protein interaction (PPI) network centrality (P < 0.05) with their NMD-escape regions enriched for PPI interfaces (P < 0.001 for −1 and nonsense) and low-complexity sequences (P < 0.03 for −1 and +1). P/LP variants also produced significantly longer mutant C-terminal tails than controls (P < 0.01), increasing potential for functional disruption. Structural modeling of altered C-terminal tails revealed recurrent gains of glycine/proline (P < 0.03) and changes in aromatic residue content consistent with altered intrinsic disorder. Integration with neurodevelopmental disorder gene sets identified 25 dosage-sensitive genes with predicted NMD-escape P/LP variants, seven (28%) encoding condensate-forming proteins. Variant-level modeling in representative genes (e.g., KAT6B ) showed altered phase-separation propensity driven by truncated and/or altered intrinsically disordered regions. Overall, this study implicates condensate dysregulation as a potential downstream biophysical consequence of NMD-escape disease alleles, providing a protein-feature viewer for variant interpretation ( https://github.com/schmidtjacob46/NMDesc-protein-viewer ).","journal":"medRxiv","year":2025,"id":584646,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1461564,"name":"Jacob Schmidt","orcid":"0000-0002-9855-6319","position":1,"is_corresponding":false},{"id":1019194,"name":"Tugce Bozkurt‐Yozgatli","orcid":null,"position":2,"is_corresponding":false},{"id":1370085,"name":"Iman Egab","orcid":null,"position":3,"is_corresponding":false},{"id":10988,"name":"Luisa Mestroni","orcid":"0000-0003-1116-2286","position":4,"is_corresponding":false},{"id":1204455,"name":"Matthew Taylor","orcid":"0000-0003-4716-4662","position":5,"is_corresponding":false},{"id":281492,"name":"Jennifer E. Posey","orcid":"0000-0003-4814-6765","position":6,"is_corresponding":false},{"id":1753,"name":"Richard A. Gibbs","orcid":"0000-0002-1356-5698","position":7,"is_corresponding":false},{"id":245381,"name":"Eric Boerwinkle","orcid":"0000-0001-8813-0544","position":8,"is_corresponding":false},{"id":286564,"name":"Paul S. de Vries","orcid":"0000-0003-0964-0111","position":9,"is_corresponding":false},{"id":51216,"name":"Alanna C. Morrison","orcid":"0000-0001-6381-4296","position":10,"is_corresponding":false},{"id":307778,"name":"Chad A. Shaw","orcid":"0000-0001-7267-5398","position":12,"is_corresponding":false},{"id":1497788,"name":"Cláudia Carvalho","orcid":"0000-0002-1937-6177","position":13,"is_corresponding":false},{"id":36511,"name":"James R. Lupski","orcid":"0000-0001-9907-9246","position":14,"is_corresponding":false},{"id":667918,"name":"Sujatha Jagannathan","orcid":"0000-0001-9039-2631","position":15,"is_corresponding":false},{"id":683684,"name":"Emel Timuçin","orcid":"0000-0003-0048-0668","position":16,"is_corresponding":false},{"id":281964,"name":"Zeynep Coban‐Akdemir","orcid":"0000-0001-9928-9032","position":17,"is_corresponding":false},{"id":1370087,"name":"Jiaoyang Xu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:16.166424Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}