A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin

Abstract

Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277-1180_1386 þ 2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.

Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome

“…For example, the existence in a Spanish series, of two MSH2 founder deletions (exon 4-8 and exon 7) doubles the rate of mutations in this gene compared to MLH1 (41). Also, a substantial enrichment of Sardinians was seen among the patients carrying MSH2 deletions (or more precisely, exon 8 deletions) in an Italian series (10/13 exon 8 deletions) (42). Further investigations proved the founder effect of two exon 8 deletions, carried by 7 and 2 of the 10 families, respectively.…”

“…Also, a substantial enrichment of Sardinians was seen among the patients carrying MSH2 deletions (or more precisely, exon 8 deletions) in an Italian series (10/13 exon 8 deletions) (42). Given the presence of these two founder mutations, 50% of LS Sardinian families carry a mutation in the MSH2 gene (42). Each deletion shared breakpoints and haplotype.…”

“…In our experience in Northern Italy, when tumor IHC is suggestive for MLH1 alterations, the germline mutation analysis starts from the MLH1 founder mutation typically found in the area (c.2269dup) (74). A similar approach is used in Sardinia for the two founder MSH2 exon 8 deletions, found to have different breakpoints (42). The benefit of founders becomes even more evident when the mutations are gross rearrangements.…”

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

“…The MLH1 c.2252_2253delAA mutation is the most frequently recurring LS mutation found in our laboratory: apart from a MSH2 exon 8 deletion with founder effect identified in 8 Sardinian families [21], the other recurrent mutations were found in 2 to 4 different families only. Overall, 21.6% of the families with a MLH1 mutation identified in our laboratory carried the c.2252_2253delAA mutation.…”

“…inherited by numerous descendants of a common ancestor, have been reported in the MMR genes associated with LS [10][11][12][13][14][15][16][17][18][19][20][21].…”