{"entity": "researcher", "timestamp": "2026-09-23T22:40:36.974Z", "family": "Chao", "given": "Hsiao-Tuan", "initials": "HT", "orcid": "0000-0002-2854-5470", "affiliations": ["Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.", "Texas Children's Hospital, Houston, Texas 77030, USA.", "Cain Pediatric Neurology Research Laboratories, Jan and Dan Duncan Neurological Research Institute, Houston, Texas 77030, USA.", "Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.", "Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.", "McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, Texas 77024, USA."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/8246a8e3e77a494082f022ec5e831bda.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/8246a8e3e77a494082f022ec5e831bda"}}, "publications": [{"entity": "publication", "iuid": "1439ad651dd840bc89fa61ac9d2add3a", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/1439ad651dd840bc89fa61ac9d2add3a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/1439ad651dd840bc89fa61ac9d2add3a"}}, "title": "Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps.", "authors": [{"family": "Bilgrav Saether", "given": "Kristine", "initials": "K"}, {"family": "Eisfeldt", "given": "Jesper", "initials": "J"}, {"family": "Bengtsson", "given": "Jesse D", "initials": "JD"}, {"family": "Lun", "given": "Ming Yin", "initials": "MY"}, {"family": "Grochowski", "given": "Christopher M", "initials": "CM", "orcid": "0000-0002-3884-7720", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/88a70acbf92744869c3e9c067f5278a6.json"}}, {"family": "Mahmoud", "given": "Medhat", "initials": "M", "orcid": "0000-0002-2553-4231", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/32766ce1fbaa42d0ad083e06294b5ef5.json"}}, {"family": "Chao", "given": "Hsiao-Tuan", "initials": "HT", "orcid": "0000-0002-2854-5470", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8246a8e3e77a494082f022ec5e831bda.json"}}, {"family": "Rosenfeld", "given": "Jill A", "initials": "JA"}, {"family": "Liu", "given": "Pengfei", "initials": "P", "orcid": "0000-0002-4177-709X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c52ef5bf8b1349de8e81166965711eb7.json"}}, {"family": "Ek", "given": "Marlene", "initials": "M"}, {"family": "Schuy", "given": "Jakob", "initials": "J"}, {"family": "Ameur", "given": "Adam", "initials": "A", "orcid": "0000-0001-6085-6749", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a8b8ce05cf7f49aeb3199b5938b9f160.json"}}, {"family": "Dai", "given": "Hongzheng", "initials": "H"}, {"family": "Undiagnosed Diseases Network", "given": "", "initials": ""}, {"family": "Hwang", "given": "James Paul", "initials": "JP"}, {"family": "Sedlazeck", "given": "Fritz J", "initials": "FJ"}, {"family": "Bi", "given": "Weimin", "initials": "W"}, {"family": "Marom", "given": "Ronit", "initials": "R"}, {"family": "Wincent", "given": "Josephine", "initials": "J"}, {"family": "Nordgren", "given": "Ann", "initials": "A", "orcid": "0000-0003-3285-4281", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/02de5158a75e4fa9a5c7b8bf417a8fea.json"}}, {"family": "Carvalho", "given": "Claudia M B", "initials": "CMB"}, {"family": "Lindstrand", "given": "Anna", "initials": "A", "orcid": "0000-0003-0806-5602", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3d28fb4cc61f4033b2ac525fed3d6b94.json"}}], "type": "journal article", "published": "2024-11-20", "journal": {"title": "Genome Res", "issn": "1549-5469", "volume": "34", "issue": "11", "pages": "1785-1797", "issn-l": "1088-9051"}, "abstract": "Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis Short-read genome sequencing (srGS) can only resolve \u223c70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the inversion breakpoint region was missing from at least one of the human reference genomes (GRCh37, GRCh38, T2T-CHM13) and a reference agnostic analysis was needed. One of these cases, an INV9 mappable only in de novo assembled lrGS data using T2T-CHM13 disrupts EHMT1 consistent with a Mendelian diagnosis (Kleefstra syndrome 1; MIM#610253). Next, by pairwise comparison between T2T-CHM13, GRCh37, and GRCh38, as well as the chimpanzee and bonobo, we show that hundreds of megabases of sequence are missing from at least one human reference, highlighting that primate genomes contribute to genomic diversity. Aligning population genomic data to these regions indicated that these regions are variable between individuals. Our analysis emphasizes that T2T-CHM13 is necessary to maximize the value of lrGS for optimal inversion detection in clinical diagnostics. These results highlight the importance of leveraging diverse and comprehensive reference genomes to resolve unsolved molecular cases in rare diseases.", "doi": "10.1101/gr.279346.124", "pmid": "39486878", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11610578"}, {"db": "pii", "key": "gr.279346.124"}, {"db": "medline", "key": "9509184"}], "notes": [], "created": "2026-09-23T13:48:47.210Z", "modified": "2026-09-23T13:48:47.384Z"}, {"entity": "publication", "iuid": "7064e79dd4f84eb7adfdecc76bd49418", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/7064e79dd4f84eb7adfdecc76bd49418.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/7064e79dd4f84eb7adfdecc76bd49418"}}, "title": "Mind the gap: the relevance of the genome reference to resolve rare and pathogenic inversions.", "authors": [{"family": "Bilgrav Saether", "given": "Kristine", "initials": "K"}, {"family": "Eisfeldt", "given": "Jesper", "initials": "J"}, {"family": "Bengtsson", "given": "Jesse", "initials": "J"}, {"family": "Lun", "given": "Ming Yin", "initials": "MY"}, {"family": "Grochowski", "given": "Christopher M", "initials": "CM"}, {"family": "Mahmoud", "given": "Medhat", "initials": "M"}, {"family": "Chao", "given": "Hsiao-Tuan", "initials": "HT", "orcid": "0000-0002-2854-5470", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8246a8e3e77a494082f022ec5e831bda.json"}}, {"family": "Rosenfeld", "given": "Jill A", "initials": "JA"}, {"family": "Liu", "given": "Pengfei", "initials": "P", "orcid": "0000-0002-4177-709X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c52ef5bf8b1349de8e81166965711eb7.json"}}, {"family": "Schuy", "given": "Jakob", "initials": "J"}, {"family": "Ameur", "given": "Adam", "initials": "A", "orcid": "0000-0001-6085-6749", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a8b8ce05cf7f49aeb3199b5938b9f160.json"}}, {"family": "Undiagnosed Diseases Network", "given": "", "initials": ""}, {"family": "Hwang", "given": "James Paul", "initials": "JP"}, {"family": "Sedlazeck", "given": "Fritz J", "initials": "FJ"}, {"family": "Bi", "given": "Weimin", "initials": "W"}, {"family": "Marom", "given": "Ronit", "initials": "R"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Carvalho", "given": "Claudia M B", "initials": "CMB"}, {"family": "Lindstrand", "given": "Anna", "initials": "A", "orcid": "0000-0003-0806-5602", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3d28fb4cc61f4033b2ac525fed3d6b94.json"}}], "type": "preprint", "published": "2024-04-24", "journal": {"title": "medRxiv", "issn-l": null}, "abstract": "Both long-read genome sequencing (lrGS) and the recently published Telomere to Telomere (T2T) reference genome provide increased coverage and resolution across repetitive regions promising heightened structural variant detection and improved mapping. Inversions (INV), intrachromosomal segments which are rotated 180\u00b0 and inserted back into the same chromosome, are a class of structural variants particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage sensitive genes in cis . Here we remapped the genome data from six individuals carrying unsolved cytogenetically detected inversions. An INV6 and INV10 were resolved using GRCh38 and T2T-CHM13. Finally, an INV9 required optical genome mapping, de novo assembly of lrGS data and T2T-CHM13. This inversion disrupted intron 25 of EHMT1, confirming a diagnosis of Kleefstra syndrome 1 (MIM#610253). These three inversions, only mappable in specific references, prompted us to investigate the presence and population frequencies of differential reference regions (DRRs) between T2T-CHM13, GRCh37, GRCh38, the chimpanzee and bonobo, and hundreds of megabases of DRRs were identified. Our results emphasize the significance of the chosen reference genome and the added benefits of lrGS and optical genome mapping in solving rearrangements in challenging regions of the genome. This is particularly important for inversions and may impact clinical diagnostics.", "doi": "10.1101/2024.04.22.24305780", "pmid": "38712270", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11071548"}, {"db": "pii", "key": "2024.04.22.24305780"}], "notes": [], "created": "2026-09-23T14:51:16.269Z", "modified": "2026-09-23T14:51:16.336Z"}]}