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We describe an infant with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) in whom chromosome analysis revealed a <jats:italic>de novo<\/jats:italic> complex balanced translocation, 46,XY,t(5;7;6)(q11.2;q32;q13)dn. Subsequent molecular characterization by whole\u2010genome sequencing (WGS) identified 23 breakpoints, delineating segments derived from four chromosomes (5;6;7;21) in ancestral or inverted orientation. One of the breakpoints disrupted a known CdLS gene, <jats:italic>NIPBL<\/jats:italic>. Further investigation revealed paternal origin of the CCR allele, clustering of the breakpoint junctions, and molecular repair signatures suggestive of a single catastrophic event. Notably, very short DNA segments (25 and 41\u2009bp) were included in the reassembled chromosomes, lending additional support that the DNA repair machinery can detect and repair such segments. Interestingly, there was an independent paternally derived miniscule complex rearrangement, possibly predisposing to subsequent genomic instability. In conclusion, we report a CCR causing a monogenic Mendelian disorder, urging WGS analysis of similar unsolved cases with suspected Mendelian disorders. Breakpoint analysis allowed for identification of the underlying molecular diagnosis and implicated chromoanagenesis in CCR formation.<\/jats:p>","DOI":"10.1002\/ajmg.a.61539","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T10:22:28Z","timestamp":1583230948000},"page":"1143-1151","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Whole\u2010genome sequencing reveals complex chromosome rearrangement disrupting <scp><i>NIPBL<\/i><\/scp> in infant with Cornelia de Lange syndrome"],"prefix":"10.1002","volume":"182","author":[{"given":"Morasha","family":"Plesser Duvdevani","sequence":"first","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem 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