Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Richard Gallon*, Rachel Phelps, Christine Hayes, Laurence Brugieres, Léa Guerrini-Rousseau, Chrystelle Colas, Martine Muleris, Neil A.J. Ryan, D. Gareth Evans, Hannah Grice, Emily Jessop, Annabel Kunzemann-Martinez, Lilla Marshall, Esther Schamschula, Klaus Oberhuber, Amedeo A. Azizi, Hagit Baris Feldman, Andreas Beilken, Nina Brauer, Triantafyllia BrozouKarin Dahan, Ugur Demirsoy, Benoît Florkin, William Foulkes, Danuta Januszkiewicz-Lewandowska, Kristi J. Jones, Christian P. Kratz, Stephan Lobitz, Julia Meade, Michaela Nathrath, Hans Jürgen Pander, Claudia Perne, Iman Ragab, Tim Ripperger, Thorsten Rosenbaum, Daniel Rueda, Tomasz Sarosiek, Astrid Sehested, Isabel Spier, Manon Suerink, Stefanie Yvonne Zimmermann, Johannes Zschocke, Gillian M. Borthwick, Katharina Wimmer, John Burn, Michael S. Jackson, Mauro Santibanez-Koref

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background & Aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype–phenotype correlations using novel MSI markers selected for instability in blood. Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%–100.0%) and specificity (95% CI 97.9%–100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Original languageEnglish
Pages (from-to)579-592.e8
Issue number4
StatePublished - Apr 2023


  • Constitutional Mutation Burden
  • Functional Test
  • Pediatric Cancer
  • Replication Error Repair


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