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We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in\u2010house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read\u2010depth data revealed a\n                    <jats:italic>de novo<\/jats:italic>\n                    complex genomic rearrangement (CGR) spanning 2.7\u2009Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short\u2010read and long\u2010read GS, and optical genome mapping (OGM). This in\u2010house CGR pipeline detected five additional rearrangements throughout the genome confirmed by orthogonal methodologies as inherited and unlikely to impact this individual's phenotype. Importantly, these catastrophic genomic events, chromoanasynthesis\u2010like, are surprisingly commonly observed in the genome, inherited and involve large regions of the genome. Moreover, such inherited CGRs often include copy\u2010number gains that partially affect disease\u2010causing genes which complicate clinical interpretation. Overall, we show the utility of short\u2010read sequencing to uncover\n                    <jats:italic>de novo<\/jats:italic>\n                    and inherited chromoanasynthesis events and established genotype\u2013phenotype correlation in a proband with multiple congenital malformations.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70153","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T07:16:31Z","timestamp":1775546191000},"page":"1832-1841","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>De Novo<\/i>\n                    <\/scp>\n                    Complex Genomic Rearrangement Spanning 2q31.1 in a Proband With Congenital Malformations: Genotype\u2013Phenotype Correlation and Development of a\n                    <scp>CGR<\/scp>\n                    Detection Pipeline"],"prefix":"10.1002","volume":"200","author":[{"given":"Katherine","family":"Helle","sequence":"first","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9072-9502","authenticated-orcid":false,"given":"Jesse D.","family":"Bengtsson","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Grochowski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Human Genome Sequencing Center, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Yin","family":"Lun","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Sudhir","sequence":"additional","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini N.","family":"Jhangiani","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz J.","family":"Sedlazeck","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Human Genome Sequencing Center, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1925-2665","authenticated-orcid":false,"given":"Neil A.","family":"Hanchard","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-298X","authenticated-orcid":false,"given":"Claudia M. 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