{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:56:00Z","timestamp":1790589360665,"version":"4.1.0"},"reference-count":14,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006662","name":"NIHR","doi-asserted-by":"publisher","award":["NIHR302478"],"award-info":[{"award-number":["NIHR302478"]}],"id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Interpretation of rare-disease genomes remains constrained by variant-centric analytical frameworks that insufficiently capture the cumulative impact of multiple variants within a gene. GenePy provides an individual-level, gene-based burden metric that integrates variant consequence, allele frequency, and zygosity into a unified quantitative score, enabling a transition from discrete variant annotation to aggregated gene-level interpretation. In the context of Genomics England (GEL), this formulation supports a panel-agnostic, genotype-to-phenotype diagnostic strategy for unresolved monogenic disorders by prioritizing genes with elevated mutational burden per individual. Here, we present a fully automated, containerized GenePy workflow deployed through Nextflow and integrated within the GEL Research Environment via the Lifebit CloudOS platform. This implementation provides scalable, secure, and governance-compliant computation of gene-level burden scores across population-scale cohorts. The workflow harmonizes variant annotation, quality control, and chunked data aggregation within modular, reproducible processes designed for high-throughput execution on cloud-native infrastructure. By enabling robust, portable, and auditable gene-level scoring across large rare-disease sequencing datasets, this framework enhances analytical resolution and supports downstream statistical prioritization, integrative phenotype matching, and hypothesis generation within genotype-to-phenotype diagnostic workflows.<\/jats:p>","DOI":"10.1093\/nargab\/lqag113","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:03:49Z","timestamp":1789473829000},"source":"Crossref","is-referenced-by-count":0,"title":["Automated GenePy gene-burden computation via a reproducible Nextflow workflow integrated with the Genomics England (GEL) Lifebit platform"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-0909","authenticated-orcid":false,"given":"Iman","family":"Nazari","sequence":"first","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine, University of Southampton , Southampton SO16 6YD ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine, University of Southampton , Southampton SO16 6YD ,","place":["United Kingdom"]},{"name":"National Institute for Health Research Southampton Biomedical Research Centre , Southampton SO16 6YD ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0348-8198","authenticated-orcid":false,"given":"James","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine, University of Southampton , Southampton SO16 6YD ,","place":["United Kingdom"]},{"name":"Department of Paediatric Gastroenterology, Southampton Children\u2019s Hospital , SouthamptonSO16 6YD,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-0869","authenticated-orcid":false,"given":"Sarah","family":"Ennis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Genomic Medicine, University of Southampton , Southampton SO16 6YD ,","place":["United Kingdom"]},{"name":"National Institute for Health Research Southampton Biomedical Research Centre , Southampton SO16 6YD ,","place":["United Kingdom"]},{"name":"Department of Human Genetics and Genomic Medicine, University of Southampton , SouthamptonSO16 6YD,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"2026092805080087600_B1","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1186\/s12859-019-2877-3","article-title":"GenePy\u2014a score for estimating gene pathogenicity in individuals using next-generation sequencing data","volume":"20","author":"Mossotto","year":"2019","journal-title":"BMC Bioinformatics"},{"key":"2026092805080087600_B2","doi-asserted-by":"publisher","first-page":"101073","DOI":"10.1016\/j.gim.2024.101073","article-title":"A gene pathogenicity tool \u2018GenePy\u2019 identifies missed biallelic diagnoses in the 100,000 Genomes Project","volume":"26","author":"Seaby","year":"2024","journal-title":"Genet Med"},{"key":"2026092805080087600_B3","unstructured":"The National Genomic Research Library, Genomics England (2024). 10.6084\/m9.figshare.4530893 \u00a0https:\/\/www.genomicsengland.co.uk\/research. Last accessed 28 August 2026."},{"key":"2026092805080087600_B4","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nbt.3820","article-title":"Nextflow enables reproducible computational workflows","volume":"35","author":"Di\u00a0Tommaso","year":"2017","journal-title":"Nat Biotechnol"},{"key":"2026092805080087600_B5","first-page":"2","article-title":"Docker: lightweight Linux containers for consistent development and deployment","volume":"2014","author":"Merkel","year":"2014","journal-title":"Linux J"},{"key":"2026092805080087600_B6","doi-asserted-by":"publisher","first-page":"e0177459","DOI":"10.1371\/journal.pone.0177459","article-title":"Singularity: scientific containers for mobility of compute","volume":"12","author":"Kurtzer","year":"2017","journal-title":"PLoS One"},{"key":"2026092805080087600_B7","article-title":"Lifebit CloudOS data intelligence platform","author":"Lifebit"},{"key":"2026092805080087600_B8","article-title":"\"Amazon Web Services (AWS).\"","author":"Amazon Web Services, Inc. 2026."},{"key":"2026092805080087600_B9","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2026092805080087600_B10","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"2026092805080087600_B11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"CADD-Splice\u2014improving genome-wide variant effect prediction using deep learning-derived splice scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med"},{"key":"2026092805080087600_B12","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/1471-2105-15-125","article-title":"Effective filtering strategies to improve data quality from population-based whole exome sequencing studies","volume":"15","author":"Carson","year":"2014","journal-title":"BMC Bioinformatics"},{"key":"2026092805080087600_B13","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41592-018-0051-x","article-title":"Strelka2: fast and accurate calling of germline and somatic variants","volume":"15","author":"Kim","year":"2018","journal-title":"Nat Methods"},{"key":"2026092805080087600_B14","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1159\/000108939","article-title":"Graphical tests for Hardy\u2013Weinberg equilibrium based on the ternary plot","volume":"65","author":"Graffelman","year":"2008","journal-title":"Hum Hered"}],"container-title":["NAR Genomics and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/8\/4\/lqag113\/71431701\/lqag113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/8\/4\/lqag113\/71431701\/lqag113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:08:09Z","timestamp":1790586489000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nargab\/article\/doi\/10.1093\/nargab\/lqag113\/8840866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":14,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,9,28]]}},"URL":"https:\/\/doi.org\/10.1093\/nargab\/lqag113","relation":{},"ISSN":["2631-9268"],"issn-type":[{"value":"2631-9268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,12]]},"published":{"date-parts":[[2026,9,28]]},"article-number":"lqag113"}}