{"doi":"10.64898/2026.01.16.26344264","title":"Systematic assessment of rare and\n                  <i>de novo</i>\n                  structural variants in 57 patient-parent trios using optical genome mapping","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Next-generation sequencing has unraveled the genetic cause for many individuals with a rare disease, but a significant number of individuals remain undiagnosed using standard of care tests. It is anticipated that structural variants (SVs) have not been fully assessed in this context. Here, we performed optical genome mapping (OGM) for 57 trios and prioritized SVs using a two-step approach. First, we systematically identified all\n                  <jats:italic>de novo</jats:italic>\n                  SVs, and subsequently we studied all rare inherited SVs. Potential pathogenic SVs were confirmed using orthogonal methods. On average, we identified 6,289 SVs &gt;500bp per proband, primarily insertions (69.8%) and deletions (27.1%). In total, we identified 13\n                  <jats:italic>de novo</jats:italic>\n                  SVs, confirming a\n                  <jats:italic>de novo</jats:italic>\n                  mutation rate for large SVs of 0.23 or 1 in 4-5 cases. These\n                  <jats:italic>de novo</jats:italic>\n                  SVs impacted multiple (candidate) disease-associated genes, including\n                  <jats:italic>NSF</jats:italic>\n                  and\n                  <jats:italic>FGF9</jats:italic>\n                  . Additionally, on average per sample, we identified 11 rare inherited SVs overlapping with an established OMIM disease gene or its regulatory region, including a homozygous deletion affecting\n                  <jats:italic>SCN9A</jats:italic>\n                  causing congenital indifference to pain, a maternally inherited deletion in\n                  <jats:italic>WWOX</jats:italic>\n                  causing developmental and epileptic encephalopathy, and an interchromosomal insertion in the CMTX3 locus at Xq27.1 causing X-linked Charcot-Marie-Tooth disease. In total, we identified pathogenic SVs in three individuals and candidate disease-causing SVs in five other individuals. Overall, OGM enabled the accurate detection of challenging\n                  <jats:italic>de novo</jats:italic>\n                  and rare inherited SVs. Our results suggest a potential yield of disease-associated SVs in 5-14% of index cases, demonstrating that OGM can unravel previously hidden SVs in extensively tested individuals.\n                </jats:p>","journal":null,"year":null,"id":630824,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1634472,"name":"Sandra Vorimo","orcid":null,"position":1,"is_corresponding":false},{"id":585388,"name":"Theresa Brunet","orcid":"0000-0002-5183-780X","position":2,"is_corresponding":false},{"id":1634475,"name":"Aïcha Boughalem","orcid":null,"position":3,"is_corresponding":false},{"id":1160776,"name":"Maureen Jacob","orcid":null,"position":4,"is_corresponding":false},{"id":1311698,"name":"Ronald van Beek","orcid":null,"position":5,"is_corresponding":false},{"id":1634477,"name":"Eveline Kamping","orcid":null,"position":6,"is_corresponding":false},{"id":912172,"name":"Elisa Rahikkala","orcid":"0000-0003-2760-7059","position":7,"is_corresponding":false},{"id":79264,"name":"Outi Kuismin","orcid":"0000-0002-0157-8985","position":8,"is_corresponding":false},{"id":1634479,"name":"Jukka Moilanen","orcid":null,"position":9,"is_corresponding":false},{"id":590679,"name":"Katri Pylkäs","orcid":"0000-0002-2449-0521","position":10,"is_corresponding":false},{"id":16952,"name":"Elisabeth Graf","orcid":"0000-0002-1119-2285","position":11,"is_corresponding":false},{"id":1634483,"name":"Sandy Loesecke","orcid":null,"position":12,"is_corresponding":false},{"id":1634484,"name":"Melanie Brugger","orcid":null,"position":13,"is_corresponding":false},{"id":1634486,"name":"Kevork Derderian","orcid":null,"position":14,"is_corresponding":false},{"id":1634489,"name":"Ulrich Schatz","orcid":null,"position":15,"is_corresponding":false},{"id":282681,"name":"Matias Wagner","orcid":"0000-0002-4454-8823","position":16,"is_corresponding":false},{"id":567695,"name":"Michael Zech","orcid":"0000-0001-8112-9153","position":17,"is_corresponding":false},{"id":1634490,"name":"Eva M.C. Schwaibold","orcid":null,"position":18,"is_corresponding":false},{"id":301284,"name":"Felix Distelmaier","orcid":"0000-0003-4304-7848","position":19,"is_corresponding":false},{"id":1015784,"name":"Ingo Borggraefe","orcid":"0000-0002-8484-5945","position":20,"is_corresponding":false},{"id":154421,"name":"Katharina Vill","orcid":null,"position":21,"is_corresponding":false},{"id":633062,"name":"Lisenka E.L.M. Vissers","orcid":"0000-0001-6470-5497","position":22,"is_corresponding":false},{"id":584745,"name":"Juliane Winkelmann","orcid":"0000-0002-2778-9027","position":23,"is_corresponding":false},{"id":57047,"name":"Kornelia Neveling","orcid":"0009-0000-8055-5329","position":24,"is_corresponding":false},{"id":11470,"name":"Thomas Meitinger","orcid":"0000-0002-8838-8403","position":25,"is_corresponding":false},{"id":1578417,"name":"Tuomo Mantere","orcid":null,"position":26,"is_corresponding":false},{"id":1634491,"name":"Detlef Trost","orcid":null,"position":27,"is_corresponding":false},{"id":57009,"name":"Alexander Hoischen","orcid":"0000-0002-8072-4476","position":28,"is_corresponding":false},{"id":1634471,"name":"Bart van der Sanden","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Systematic assessment of rare and\n                  <i>de novo</i>\n                  structural variants in 57 patient-parent trios using optical genome mapping","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Next-generation sequencing has unraveled the genetic cause for many individuals with a rare disease, but a significant number of individuals remain undiagnosed using standard of care tests. It is anticipated that structural variants (SVs) have not been fully assessed in this context. Here, we performed optical genome mapping (OGM) for 57 trios and prioritized SVs using a two-step approach. First, we systematically identified all\n                  <jats:italic>de novo</jats:italic>\n                  SVs, and subsequently we studied all rare inherited SVs. Potential pathogenic SVs were confirmed using orthogonal methods. On average, we identified 6,289 SVs &gt;500bp per proband, primarily insertions (69.8%) and deletions (27.1%). In total, we identified 13\n                  <jats:italic>de novo</jats:italic>\n                  SVs, confirming a\n                  <jats:italic>de novo</jats:italic>\n                  mutation rate for large SVs of 0.23 or 1 in 4-5 cases. These\n                  <jats:italic>de novo</jats:italic>\n                  SVs impacted multiple (candidate) disease-associated genes, including\n                  <jats:italic>NSF</jats:italic>\n                  and\n                  <jats:italic>FGF9</jats:italic>\n                  . Additionally, on average per sample, we identified 11 rare inherited SVs overlapping with an established OMIM disease gene or its regulatory region, including a homozygous deletion affecting\n                  <jats:italic>SCN9A</jats:italic>\n                  causing congenital indifference to pain, a maternally inherited deletion in\n                  <jats:italic>WWOX</jats:italic>\n                  causing developmental and epileptic encephalopathy, and an interchromosomal insertion in the CMTX3 locus at Xq27.1 causing X-linked Charcot-Marie-Tooth disease. In total, we identified pathogenic SVs in three individuals and candidate disease-causing SVs in five other individuals. Overall, OGM enabled the accurate detection of challenging\n                  <jats:italic>de novo</jats:italic>\n                  and rare inherited SVs. Our results suggest a potential yield of disease-associated SVs in 5-14% of index cases, demonstrating that OGM can unravel previously hidden SVs in extensively tested individuals.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W7125424836","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by-nd","oa_locations":[{"url":"https://www.medrxiv.org/content/medrxiv/early/2026/01/21/2026.01.16.26344264.full.pdf","host_type":"repository"},{"url":"https://www.medrxiv.org/content/medrxiv/early/2026/01/21/2026.01.16.26344264.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.01.16.26344264","host_type":"publisher"},{"url":"https://doi.org/10.64898/2026.01.16.26344264","host_type":"repository"}],"fields_of_study":["Genomics and Rare Diseases","Genomic variations and chromosomal abnormalities","Genomics and Phylogenetic Studies"],"mesh_terms":[],"keywords":["Locus (genetics)","Disease gene identification","Gene","Genome-wide association study","Genome","Candidate gene","Structural variation","Whole genome sequencing","DNA sequencing"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-05T22:14:02.374867Z","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":[]}