Abstract
Background:
Lynch syndrome is due to error in DNA mismatch repair (MMR) genes caused by germline pathogenic variants. For some families highly suspicious of Lynch syndrome, the diagnosis may not be confirmed.
Case presentation:
We present a family where Lynch syndrome has been suspected for 20 years. Although haplotyping and tumor analyses suggested Lynch syndrome, newer sequencing methods such as whole-genome sequencing and long-read sequencing, were needed to detect the underlying genetic cause of their cancer predisposition. We identified a > 3kbp retrotransposon (RT) insertion in MSH6 to be the causative germline variant. Further, we reviewed the literature for RT events in Lynch syndrome families and found a total of 40 RT cases, making up about 0.5% of Lynch cases. Two-third of the RTs were shorter ALU-elements (< 500 bp).
Conclusions:
Although RTs insertions do not seem to be a common cause of Lynch syndrome, the number might be underestimated because of the difficulties in detecting these variants with well-established methods like Sanger sequencing and NGS target sequencing.
Keywords:
Long-read sequencing; Lynch syndrome; Retrotransposons; Whole genome sequencing.