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

Abstract

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.

Keywords: childhood cancer; constitutional mismatch repair deficiency; founder variant; microsatellite instability; neurofibromatosis type 1.

Fig. 1. Workflow of the constitutional mismatch repair deficiency (CMMRD) screening pipeline and summary of results.

The number of patients and their outcomes are presented in gray boxes, assays used in the screening pipeline are presented in white boxes, criteria by which the assay results were assessed are presented in rhombi, and additional assessments are presented in ovals. gDNA genomic DNA, gMSI germline MSI, MSI microsatellite instability, MUI Medical University of Innsbruck, QC quality control, UAB University of Alabama–Birmingham.