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While this approach aids reliable bioinformatic detection of short coding variants, it often fails to detect many larger variants. Recent studies have recommended the adoption of pangenome references (as opposed to linear reference genomes like GRCh38) to augment detection of large variants from targeted sequencing, potentially providing diagnostic laboratories with the possibility to streamline diagnostic work-ups and reduce costs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we analyze 1969 cardiomyopathy cases and 1805 controls sequenced with the Illumina Trusight Cardio panel using a pangenome-based workflow (GRAF) and five conventional orthogonal methodologies (GATK HaplotypeCaller, GATK-gCNV, ExomeDepth, Manta and Lumpy-SV) to detect variants \u2265\u200920\u00a0bp in size.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following lab-based variant validation by means of PCR and Sanger sequencing, we show that GRAF conjugates higher precision and recall (F1 score 0.86) compared with other methods (F1 0-0.57) in detecting potentially pathogenic variants \u2265\u200920\u00a0bp from short-read panel data. Results were complemented by a comparison of the tools\u2019 performance in detecting ground truth variants on reference sample HG002 from Genome In A Bottle, which confirmed GRAF to outperform other tools also on exome sequencing (F1 0.97 vs. 0-0.94). Notably, in the HG002 benchmark dataset, GRAF also showed slightly improved performance compared to GATK HaplotypeCaller in the identification of small variants (1\u201319\u00a0bp; F1 0.975 vs. 0.968).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results indicate that pangenome-based workflows aid improved detection of large variants from targeted sequencing data in the clinical context and suggest that they may contribute to more unified variant detection frameworks for all-size genetic variants in the future.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01749-0","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T01:06:07Z","timestamp":1787706367000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pangenomes aid accurate detection of large insertions and deletions from targeted sequencing: the case of cardiomyopathies"],"prefix":"10.1186","volume":"18","author":[{"given":"Francesco","family":"Mazzarotto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zem","family":"Kalay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Arslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Cinquina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel J.","family":"Buchan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Bertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esm\u00e9","family":"Cavanagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Turgut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Allouba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Afify","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Halawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pantazis","family":"Theotokis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gungor","family":"Budak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Girolami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Azzu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Peldova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nik","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dudley J.","family":"Pennell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Bonaventura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Olivotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Pelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Colombi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Macek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. 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Specifically, for London samples, ethical approval was given by the Hampshire B Research Ethics Committee (09\/H0504\/104\u2009+\u20095 and 19\/SC\/0257) and by the London - West London & GTAC Research Ethics Committee (09\/H0707\/69). For Prague samples, approval was given by the IRB of Motol University Hospital (Reference No. EK-323\/23). For Aswan samples, approval was given by the Local Research Ethics Committee (registered with the Egypt Ministry of Health, the US Department of Health and Human Services (HHS) Institutional Review Board (IRB) and the Federal wide Assurance for the Protection of Human Subject (FWA)), with approval number 20130405MYFAHC_CMR_20130330. For Florence samples, approval was waived by the Comitato Etico Area Vasta Centro (CEAVC) based on the informed consent for anonymized research use of the DNA sample given by each patient when referred for genetic testing at the Careggi University Hospital.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"O.K., E.A., D.T., G.B., S.T. and A.J. are (or were, at the time this study was in development) employees of Seven Bridges Genomics or Velsera Inc, the commercial companies that developed GRAF (one of the approached utilized to analyze the data). The remaining authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"132"}}