Recurrent germline mutation in MSH2 arises frequently de novo

• Published in: Journal of Medical Genetics
• Main Authors: Desai DC, Lockman JC, Chadwick RB, Gao X, PERCESEPE, Antonio, Evans DGR, Miyaki M, Yuen ST, Radice P, Maher ER, Wright FA, de la Chapelle A.
• Other Authors: Desai, Dc, Lockman, Jc, Chadwick, Rb, Gao, X, Percesepe, Antonio, Evans, Dgr, Miyaki, M, Yuen, St, Radice, P, Maher, Er, Wright, Fa, de la Chapelle, A.
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2000
• Subjects: MSH2; recurrent mutation; splice donor site of exon 5; founder mutation; Newfoundland
• Online Access: http://hdl.handle.net/11380/7005; https://doi.org/10.1136/jmg.37.9.646

Introduction-An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. Methods-We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and rnicrosatellite markers. Results-Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. Discussion-As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSN2 mutations.