Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome caused by changes in the APC gene, but approximately 20% of patients remain unsolved after routine diagnostics. In this work, we applied multidimensional genomic analyses to solve a case of FAP after more than 20 years. We identified a complex genomic rearrangement disrupting several coding genes and resulting in downregulation of APC mRNA expression. Our findings broaden the spectrum of known genetic mechanisms underlying FAP that may increase diagnostic yield in the future. Additionally, the stepwise analytical strategy we developed can serve as blueprint for integration into a routine diagnostic workflow. (By Florentine Scharf, https://jmg.bmj.com/content/early/2021/12/13/jmedgenet-2021-108147 )