title: Origins and prevalence of the American Founder Mutation of MSH2.
abstract: 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.
authors.affiliation: Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Mark E
authors.initials: ME
authors.lastname: Baze
authors.forename: Shuying
authors.initials: S
authors.lastname: Sun
authors.forename: Kyle
authors.initials: K
authors.lastname: Walsh
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Dan
authors.initials: D
authors.lastname: Fix
authors.forename: Victoria
authors.initials: V
authors.lastname: Schunemann
authors.forename: Ilene
authors.initials: I
authors.lastname: Comeras
authors.forename: Molly
authors.initials: M
authors.lastname: Deacon
authors.forename: Jane F
authors.initials: JF
authors.lastname: Lynch
authors.forename: Gordon
authors.initials: G
authors.lastname: Gong
authors.forename: Brittany C
authors.initials: BC
authors.lastname: Thomas
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D015995:Prevalence; D014481:United States / Q000453:epidemiology
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein