Gallon, Richard ORCID: 0000-0002-5395-0099, Muehlegger, Barbara, Wenzel, Soeren-Sebastian, Sheth, Harsh, Hayes, Christine, Aretz, Stefan ORCID: 0000-0002-5228-1890, Dahan, Karin, Foulkes, William, Kratz, Christian P., Ripperger, Tim, Azizi, Amedeo A., Feldman, Hagit Baris, Chong, Anne-Laure, Demirsoy, Ugur, Florkin, Benoit, Imschweiler, Thomas, Januszkiewicz-Lewandowska, Danuta ORCID: 0000-0003-2332-2750, Lobitz, Stephan ORCID: 0000-0001-5398-0610, Nathrath, Michaela, Pander, Hans-Juergen, Perez-Alonso, Vanesa, Perne, Claudia, Ragab, Iman, Rosenbaum, Thorsten, Rueda, Daniel ORCID: 0000-0002-5377-8890, Seidel, Markus G. ORCID: 0000-0003-0981-8661, Suerink, Manon, Taeubner, Julia, Zimmermann, Stefanie-Yvonne, Zschocke, Johannes, Borthwick, Gillian M., Burn, John, Jackson, Michael S., Santibanez-Koref, Mauro and Wimmer, Katharina (2019). A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes. Hum. Mutat., 40 (5). S. 649 - 656. HOBOKEN: WILEY. ISSN 1098-1004

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gallon, RichardUNSPECIFIEDorcid.org/0000-0002-5395-0099UNSPECIFIED
Muehlegger, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, Soeren-SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sheth, HarshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hayes, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aretz, StefanUNSPECIFIEDorcid.org/0000-0002-5228-1890UNSPECIFIED
Dahan, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foulkes, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kratz, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ripperger, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azizi, Amedeo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feldman, Hagit BarisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chong, Anne-LaureUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demirsoy, UgurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florkin, BenoitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imschweiler, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Januszkiewicz-Lewandowska, DanutaUNSPECIFIEDorcid.org/0000-0003-2332-2750UNSPECIFIED
Lobitz, StephanUNSPECIFIEDorcid.org/0000-0001-5398-0610UNSPECIFIED
Nathrath, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pander, Hans-JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Alonso, VanesaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perne, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ragab, ImanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenbaum, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueda, DanielUNSPECIFIEDorcid.org/0000-0002-5377-8890UNSPECIFIED
Seidel, Markus G.UNSPECIFIEDorcid.org/0000-0003-0981-8661UNSPECIFIED
Suerink, ManonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taeubner, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimmermann, Stefanie-YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zschocke, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borthwick, Gillian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burn, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, Michael S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santibanez-Koref, MauroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wimmer, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-149839
DOI: 10.1002/humu.23721
Journal or Publication Title: Hum. Mutat.
Volume: 40
Number: 5
Page Range: S. 649 - 656
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EUROPEAN CONSORTIUM CARE; SURVEILLANCE; MUTATION; RECOMMENDATIONS; MANAGEMENT; DEFECT; GENESMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14983

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item