Detecting inversions in routine molecular diagnosis in MMR genes

• Published in: Familial cancer Vol. 21; no. 4; pp. 423 - 428
• Main Authors: Kasper, Edwige, Coutant, Sophie, Manase, Sandrine, Vasseur, Stéphanie, Macquère, Pierre, Bougeard, Gaëlle, Faivre, Laurence, Ingster, Olivier, Baert-Desurmont, Stéphanie, Houdayer, Claude
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2022; Springer Nature B.V; Springer Verlag (Germany)
• Subjects: Alternative splicing; Biomedical and Life Sciences; Biomedicine; Cancer Research; Colon cancer; Colonic Neoplasms; Colorectal cancer; Colorectal Neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Diagnosis; DNA Mismatch Repair; DNA Mismatch Repair - genetics; DNA-Binding Proteins; DNA-Binding Proteins - genetics; Epidemiology; Gene expression; Genetic disorders; Genomics; Human Genetics; Humans; Life Sciences; Mismatch repair; Mismatch Repair Endonuclease PMS2; Mismatch Repair Endonuclease PMS2 - genetics; MSH6 protein; MutL Protein Homolog 1; MutL Protein Homolog 1 - genetics; MutS Homolog 2 Protein; MutS Homolog 2 Protein - genetics; Neoplastic Syndromes, Hereditary; Original Article; Whole-gene panel; Inversions; MSH6; PMS2
• ISSN: 1389-9600; 1573-7292
• DOI: 10.1007/s10689-021-00287-5

Inversions, i.e. a change in orientation of a segment of DNA, are a recognized cause of human diseases which remain overlooked due to their balanced nature. Inversions can have severe or more subtle impacts on gene expression. We describe two families that exemplify these aspects and underline the need for inversion detection in routine diagnosis. The first family (F1) displayed a sibship with two constitutional mismatch repair deficiency patients and a family history of colon cancer in the paternal branch. The second family (F2) displayed a severe history of Lynch syndrome. These families were analyzed using a whole gene panel (WGP) strategy i.e. including colon cancer genes with their intronic and flanking genomic regions. In F1, a PMS2 inversion encompassing the promoter region to intron 1 and a PMS2 splice variant were found in the maternal and paternal branch, respectively. In F2, we described the first MSH6 inversion, involving the 5′ part of MSH6 and the 3′ part of the nearby gene ANXA4 . Inversion detection mandates genomic sequencing, but makes a valuable contribution to the diagnostic rate. WGP is an attractive strategy as it maximizes the detection power on validated genes and keeps sufficient depth to detect de novo events.