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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.
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
URL: https://doi.org/10.1038/s41436-020-0925-z
DOI: 10.1038/s41436-020-0925-z
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