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1. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes.

Author

Gallon R, Mühlegger B, Wenzel SS, Sheth H, Hayes C, Aretz S, Dahan K, Foulkes W, Kratz CP, Ripperger T, Azizi AA, Baris Feldman H, Chong AL, Demirsoy U, Florkin B, Imschweiler T, Januszkiewicz-Lewandowska D, Lobitz S, Nathrath M, Pander HJ, Perez-Alonso V, Perne C, Ragab I, Rosenbaum T, Rueda D, Seidel MG, Suerink M, Taeubner J, Zimmermann SY, Zschocke J, Borthwick GM, Burn J, Jackson MS, Santibanez-Koref M, and Wimmer K

Subjects
Alleles, Germ-Line Mutation, Humans, Microsatellite Repeats, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, DNA Mismatch Repair, Genetic Association Studies methods, Genetic Predisposition to Disease, Leukocytes metabolism, Microsatellite Instability, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics
Abstract

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Published
2019
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2. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes

Author

Gallon, R., Muhlegger, B., Wenzel, S.S., Sheth, H., Hayes, C., Aretz, S., Dahan, K., Foulkes, W., Kratz, C.P., Ripperger, T., Azizi, A.A., Feldman, H.B., Chong, A.L., Demirsoy, U., Florkin, B., Imschweiler, T., Januszkiewicz-Lewandowska, D., Lobitz, S., Nathrath, M., Pander, H.J., Perez-Alonso, V., Perne, C., Ragab, I., Rosenbaum, T., Rueda, D., Seidel, M.G., Suerink, M., Taeubner, J., Zimmermann, S.Y., Zschocke, J., Borthwick, G.M., Burn, J., Jackson, M.S., Santibanez-Koref, M., and Wimmer, K.

Subjects
Brain Neoplasms, next‐generation sequencing, DNA Mismatch Repair, Neoplastic Syndromes, Hereditary, Leukocytes, Methods, Humans, Genetic Predisposition to Disease, microsatellite instability, next-generation sequencing, single molecule molecular inversion probes, genetic diagnostics, Colorectal Neoplasms, variant classification, Constitutional mismatch repair deficiency, Alleles, Genetic Association Studies, Germ-Line Mutation, Microsatellite Repeats
Abstract

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low‐level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low‐frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically‐confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at‐risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

Published
2019

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