{"doi":"10.1101/2025.07.16.665183","title":"Aberrant splicing prediction during human organ development","abstract":"Developmental disorders constitute a major class of genetic diseases, yet tools to identify splicing-disruptive variants during development are lacking. To address this need we extended the AbSplice framework to incorporate splicing dynamics across developmental stages. Moreover, we introduced several improvements including a refined ground truth from the aberrant splicing caller FRASER2, a continuous representation of splice site usage, and integration of the rich set of predictions from the sequence-based model Pangolin. These advances improve the performance of the original model at predicting aberrant splicing events and enable predictions across embryonic, childhood, and adult tissues. Genome-wide scores for all single-nucleotide variants and a web interface to score indels are available to facilitate the exploration of the predictions. Our genome-wide predictions reveal a class of variants with splicing-disruptive effects confined to early development, particularly abundant in the brain (>18,000 variants). These variants are enriched in loss-of-function intolerant genes and neurodevelopmental disorder genes. Within the rare-disease cohort Solve-RD high-impact brain-specific predictions are significantly enriched in individuals affected by neurodevelopmental disorders (NDD) in NDD-linked genes. Furthermore, the predicted developmental timing of the splicing disruption correlates with the clinical age of onset. Analysis of genomes of individuals with a suspected Mendelian disorder from Genomics England identified 26 unique variants in disease-linked genes, with stronger predicted effects during development than in adulthood, including a candidate new diagnosis in the gene FGFR1 . Altogether, these results improve the accuracy of splice-disruptive variant prediction and provide tissue and developmental context to aid interpretation in rare disease diagnostics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":570535,"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":0.8921,"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":1476116,"name":"Александр Неверов","orcid":null,"position":1,"is_corresponding":false},{"id":1165196,"name":"Alexandra C Martin-Geary","orcid":"0000-0002-5818-1962","position":2,"is_corresponding":false},{"id":1475763,"name":"Shubhankar Londhe","orcid":"0000-0002-1220-6650","position":3,"is_corresponding":false},{"id":1476117,"name":"Carina Schröder","orcid":null,"position":4,"is_corresponding":false},{"id":50557,"name":"Vicente A. Yépez","orcid":"0000-0001-7916-3643","position":5,"is_corresponding":false},{"id":990,"name":"Nicola Whiffin","orcid":"0000-0003-1554-6594","position":6,"is_corresponding":false},{"id":249406,"name":"Julien Gagneur","orcid":"0000-0002-8924-8365","position":7,"is_corresponding":false},{"id":985847,"name":"Nils Wagner","orcid":"0009-0006-5661-1646","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:07.857542Z","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":[]}