Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA

Hum Mutat. 2003 Dec;22(6):428-33. doi: 10.1002/humu.10291.


Gene dosage abnormalities account for a significant proportion of the mutations in genes tested in DNA diagnostic laboratories. Detection of these changes has proved a challenge as the methods available to date are time consuming or unreliable. The multiplex ligation-dependent probe assay (MLPA) is a new technique allowing relative quantification of up to 40 different nucleic acid sequences in a single reaction tube. We have evaluated MLPA for potential use in the diagnostic setting against the following criteria: accuracy, reagent cost, hands-on time, reliability, and retests required. A total of 215 UK patients referred for genetic testing on the basis of a family history consistent with autosomal dominant hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) were tested by MLPA. Of these, 12 cases with deletions of one or more exons were identified, six with MLH1 deletions and six with MSH2 deletions. Test failure rates were less than 5% and overall mutation detection sensitivity in this series was increased by approximately 50% by the inclusion of MLPA for an additional testing cost of about 10%. Two novel mutations in MSH2 and 10 novel point mutations in MLH1 were also identified during the course of this study. We conclude that MLPA is a cost effective and robust gene dosage method that can be readily adopted by diagnostic services. Comprehensive mutation scanning for MSH2 and MLH1 is incomplete without gene dosage analysis.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Mutational Analysis / methods*
  • DNA Repair
  • DNA-Binding Proteins*
  • Exons / genetics
  • Gene Deletion*
  • Haplotypes
  • Humans
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Point Mutation
  • Proto-Oncogene Proteins / genetics*
  • Reproducibility of Results
  • Sensitivity and Specificity


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein