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Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1

Lookup NU author(s): Dr Richard Gallon, Dr Michael Jackson, Dr Mauro Santibanez Koref



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2020, The Author(s). Purpose: Biallelic germline mismatch repair (MMR) gene pathogenic variants (PVs) cause constitutional MMR deficiency (CMMRD), a highly penetrant childhood cancer syndrome phenotypically overlapping with neurofibromatosis type 1 (NF1). CMMRD testing in suspected NF1 children without NF1/SPRED1 PVs enables inclusion of CMMRD positives into monitoring programs prior to tumor onset. However, testing is associated with potential harms and the prevalence of CMMRD among these children is unknown. Methods: Using a simple and scalable microsatellite instability (MSI) assay of non-neoplastic leukocyte DNA to detect CMMRD, we retrospectively screened >700 children suspected of sporadic NF1 but lacking NF1/SPRED1 PVs. Results: For three of seven MSI-positive patients germline MMR gene PVs confirmed the diagnosis of CMMRD. Founder variants NM_000535.5(PMS2):c.736_741delinsTGTGTGTGAAG, prevalent in Europe and North America, and NM_000179.2(MSH6):c.10C>G, affecting 1:400 French Canadians, represented two of five PVs. The prevalence of CMMRD was 3/735 (0.41%, 95% confidence interval [CI]: 0.08–1.19%). Conclusion: Our empirical data provide reliable numbers for genetic counseling and confirm previous prevalence estimations, on which Care for CMMRD consortium guidelines are based. These advocate CMMRD testing of preselected patients rather than offering reflex testing to all suspected sporadic NF1 children lacking NF1/SPRED1 PVs. The possibility of founder effects should be considered alongside these testing guidelines.

Publication metadata

Author(s): Perez-Valencia JA, Gallon R, Chen Y, Koch J, Keller M, Oberhuber K, Gomes A, Zschocke J, Burn J, Jackson MS, Santibanez-Koref M, Messiaen L, Wimmer K

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Pages: 2081-2088

Print publication date: 01/12/2020

Online publication date: 10/08/2020

Acceptance date: 22/07/2020

Date deposited: 21/06/2021

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Springer Nature


DOI: 10.1038/s41436-020-0925-z


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Funder referenceFunder name
KLI 734-B26