Beschreibung:
<jats:sec><jats:title>Purpose</jats:title><jats:p>Approximately 20% of patients with clinical familial adenomatous polyposis (FAP) remain unsolved after molecular genetic analysis of the <jats:italic>APC</jats:italic> and other polyposis genes, suggesting additional pathomechanisms.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We applied multidimensional genomic analysis employing chromosomal microarray profiling, optical mapping, long-read genome and RNA sequencing combined with FISH and standard PCR of genomic and complementary DNA to decode a patient with an attenuated FAP that had remained unsolved by Sanger sequencing and multigene panel next-generation sequencing for years.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified a complex 3.9 Mb rearrangement involving 14 fragments from chromosome 5q22.1q22.3 of which three were lost, 1 reinserted into chromosome 5 and 10 inserted into chromosome 10q21.3 in a seemingly random order and orientation thus fulfilling the major criteria of chromothripsis. The rearrangement separates <jats:italic>APC</jats:italic> promoter 1B from the coding ORF (open reading frame) thus leading to allele-specific downregulation of <jats:italic>APC</jats:italic> mRNA. The rearrangement also involves three additional genes implicated in the <jats:italic>APC</jats:italic>–Axin–GSK3B–β-catenin signalling pathway.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening <jats:italic>APC</jats:italic> expression, possibly modified by additional <jats:italic>APC</jats:italic>–Axin–GSK3B–β-catenin pathway disruptions, underlies the patient’s clinical phenotype. The combinatorial approach we deployed provides a powerful tool set for deciphering unsolved familial polyposis and potentially other tumour syndromes and monogenic diseases.</jats:p></jats:sec>