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Novel tools and methods are needed to improve the detection of disease\u2010associated variants and understand the genetic basis of many rare diseases. Long\u2010read genome sequencing provides improved sequencing in highly repetitive, homologous, and low\u2010complexity regions, and improved assessment of structural variation and complex genomic rearrangements compared to short\u2010read genome sequencing. As such, it is a promising method to explore overlooked genetic variants in rare diseases with a high suspicion of a genetic basis. We therefore applied PacBio HiFi sequencing in a large multi\u2010generational family presenting with autosomal dominant 46,XY differences of sexual development (DSD), for whom extensive molecular testing over multiple decades had failed to identify a molecular diagnosis. This revealed a rare SINE\u2010VNTR\u2010Alu retroelement insertion in intron 4 of <jats:italic>NR5A1<\/jats:italic>, a gene in which loss\u2010of\u2010function variants are an established cause of 46,XY DSD. The insertion segregated among affected family members and was associated with loss\u2010of\u2010expression of alleles in <jats:italic>cis<\/jats:italic>, demonstrating a functional impact on <jats:italic>NR5A1.<\/jats:italic> This case highlights the power of long\u2010read genome sequencing to detect genomic variants that have previously been intractable to detection by standard short\u2010read genomic testing.<\/jats:p>","DOI":"10.1002\/ajmg.a.63522","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T09:11:36Z","timestamp":1703236296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Long\u2010read genome sequencing reveals a novel intronic retroelement insertion in <scp><i>NR5A1<\/i><\/scp> associated with 46,<scp>XY<\/scp> differences of sexual development"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7368-0033","authenticated-orcid":false,"given":"Giulia F.","family":"Del Gobbo","sequence":"first","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Couse","sequence":"additional","affiliation":[{"name":"Centre for Computational Medicine The Hospital for Sick Children  Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layla","family":"Mackay","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Canada"},{"name":"Department of Genetics Children's Hospital of Eastern Ontario  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Goldsmith","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Canada"},{"name":"Department of Genetics Children's Hospital of Eastern Ontario  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2803-0941","authenticated-orcid":false,"given":"Aren E.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa  Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijing","family":"Liang","sequence":"additional","affiliation":[{"name":"Centre for Computational Medicine The Hospital for Sick Children  Toronto 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