10-15% of patients suspected of Lynch-syndrome are mutation-negative in routine diagnostics. We identified the first paracentric inversion between the flanking genes MLH1 and LRRFIP2 flipping the genomic configuration without exonic deletion in creating two novel fusion transcripts, which even camouflaged monoallelic MLH1-deficiency when analysing only one common SNP in MLH1. Only insisting detailed analysis of the MLH1-gene deciphers the inversion, which was found in 4 family members with tumor diagnosis.
A second case revealed a large genomic intrachromosomal duplication of the MLH1 gene region including neighbouring genes TRANK1 (LBA1) and EPM2AIP1 upstream and downstream LRRFIP2 and partially GOLGA4 leaving the MLH1 gene per se intact. The low-level MLH1 promoter hypermethylation of 10%-25% which was found in different tissues of all three duplication carriers seems to result from the duplication, induced by a so far unknown mechanism and seems to be disease causing
Lessons to learn: Regulatory repression might be mediated by fusion transcripts or genomic environment which implies that families highly suspicious of Lynch-Syndrome need detailed molecular testing and despite possibly negative results, thorough clinical management. (By Monika Morak, http://jmg.bmj.com/content/early/2011/06/28/jmedgenet-2011-100050.abstract?papetoc )