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Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>As part of the Utah NeoSeq project, we used a research\u2010based, rapid whole\u2010genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left\u2010sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using both a novel, alignment\u2010free and traditional alignment\u2010based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the <jats:italic>ZFPM2<\/jats:italic> gene, which is associated with both CDH and various congenital heart defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short\u2010read sequencing and underscore the utility of WGS as a first\u2010line diagnostic tool.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1888","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T10:44:29Z","timestamp":1643971469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comprehensive variant calling from whole\u2010genome sequencing identifies a complex inversion that disrupts 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