Simple detection of germline microsatellite instability for diagnosis of constitutional mismatch repair cancer syndrome

Hum Mutat. 2013 Jun;34(6):847-52. doi: 10.1002/humu.22311. Epub 2013 Apr 2.


Heterozygous mutations in DNA mismatch repair (MMR) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or Lynch syndrome). Patients with biallelic mutations in these genes, however, present earlier, with constitutional mismatch repair deficiency cancer syndrome (CMMRD), which is characterized by a spectrum of rare childhood malignancies and café-au-lait skin patches. The hallmark of MMR deficiency, microsatellite instability (MSI), is readily detectable in tumor DNA in Lynch syndrome, but is also present in constitutional DNA of CMMRD patients. However, detection of constitutional or germline MSI (gMSI) has hitherto relied on technically difficult assays that are not routinely applicable for clinical diagnosis. Consequently, we have developed a simple high-throughput screening methodology to detect gMSI in CMMRD patients based on the presence of stutter peaks flanking a dinucleotide repeat allele when amplified from patient blood DNA samples. Using the three different microsatellite markers, the gMSI ratio was determined in a cohort of normal individuals and 10 CMMRD patients, with biallelic germline mutations in PMS2 (seven patients), MSH2 (one patient), or MSH6 (two patients). Subjects with either PMS2 or MSH2 mutations were easily identified; however, this measure was not altered in patients with CMMRD due to MSH6 mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Alleles
  • Case-Control Studies
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Computational Biology / methods
  • DNA Mismatch Repair*
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics
  • Early Detection of Cancer
  • Germ-Line Mutation*
  • Humans
  • Microsatellite Instability*
  • Microsatellite Repeats
  • Mismatch Repair Endonuclease PMS2
  • MutS Homolog 2 Protein / genetics
  • Reproducibility of Results
  • Software


  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes