Origins and prevalence of the American Founder Mutation of MSH2.


Journal Article

Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of approximately 500 years (95% confidence interval, 425-625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted.

Full Text

Duke Authors

Cited Authors

  • Clendenning, M; Baze, ME; Sun, S; Walsh, K; Liyanarachchi, S; Fix, D; Schunemann, V; Comeras, I; Deacon, M; Lynch, JF; Gong, G; Thomas, BC; Thibodeau, SN; Lynch, HT; Hampel, H; de la Chapelle, A

Published Date

  • April 1, 2008

Published In

Volume / Issue

  • 68 / 7

Start / End Page

  • 2145 - 2153

PubMed ID

  • 18381419

Pubmed Central ID

  • 18381419

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-07-6599


  • eng

Conference Location

  • United States