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. 2023 Jun;11(6):e2151.
doi: 10.1002/mgg3.2151. Epub 2023 Feb 9.

Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome

Dennis Witt  1 , Ulrike Faust  1 , Gertrud Strobl-Wildemann  2 , Marc Sturm  1 , Rebecca Buchert  1 , Theresia Zuleger  1 , Jakob Admard  1 , Nicolas Casadei  1   3 , Stephan Ossowski  1 , Tobias B Haack  1 , Olaf Rieß  1 , Christopher Schroeder  1
Affiliations

Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome

Dennis Witt et al. Mol Genet Genomic Med. 2023 Jun.

Abstract

Background: Lynch syndrome is one of the most common cancer predisposition syndromes. It is caused by inherited changes in the mismatch repair pathway. With current diagnostic approaches, a causative genetic variant can be found in less than 50% of cases. A correct diagnosis is important for ensuring that an appropriate surveillance program is used and that additional high-risk family members are identified.

Methods: We used clinical genome sequencing on DNA from blood and subsequent transcriptome sequencing for confirmation. Data were analyzed using the megSAP pipeline and classified according to basic criteria in diagnostic laboratories. Segregation analyses in family members were conducted via breakpoint PCR.

Results: We present a family with the clinical diagnosis of Lynch syndrome in which standard diagnostic tests, such as panel or exome sequencing, were unable to detect the underlying genetic variant. Genome sequencing in the index patient confirmed the previous diagnostic results and identified an additional complex rearrangement with intronic breakpoints involving MLH1 and its neighboring gene LRRFIP2. The previously undetected structural variant was classified as medically relevant. Segregation analysis in the family identified additional at-risk individuals which were offered intensified cancer screening.

Discussion and conclusions: This case illustrates the advantages of clinical genome sequencing in detecting structural variants compared with current diagnostic approaches. Although structural variants are rare in Lynch syndrome families, they seem to be underreported, in part because of technical challenges. Clinical genome sequencing offers a comprehensive genetic characterization detecting a wide range of genetic variants.

Keywords: MLH1; HNPCC; Lynch syndrome; copy-number neutral; genome-sequencing; structural variant.

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Conflict of interest statement

There are no competing interests.

Figures

FIGURE 1
FIGURE 1
Pedigree. This figure presents the families' pedigree. Persons suffering from cancer are marked black. Subjects tested for the identified MLH1 variation are marked by an asterisk.
FIGURE 2
FIGURE 2
Genomic fragmentation and breakpoint PCR. Panel A presents the information shown in IGV, while panel B illustrates the subsequent interpretation of this information and the position of the breakpoint PCR amplicons. G1 and G2 represent the unaltered genomic fragments. The complex variant includes an inversion of fragment R and a loss of fragment P as well as an insertion of the fragment marked in yellow (TGGTA). The deletion of fragment P was identified solely due to context and reduction in copy number. This genomic variant is leading to two stable in‐frame fusion transcripts that include MLH1 exons 1–15 and LRRFIP2 exon 29 and LRRFIP2 exon 1–3 fused with MLH1 exons 16–19.
See this image and copyright information in PMC

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