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Robust detection of somatic mosaicism and repeat interruptions by long-read targeted sequencing in myotonic dystrophy Type 1

Mangin, Antoine, de Pontual, Laure, Tsai, Yu-Chih, Monteil, Laetitia, Nizon, Mathilde, Boisseau, Pierre, Mercier, Sandra, Ziegle, Janet, Harting, John, Heiner, Cheryl, Gourdon, Geneviève and Tomé, Stéphanie 2021. Robust detection of somatic mosaicism and repeat interruptions by long-read targeted sequencing in myotonic dystrophy Type 1. International Journal of Molecular Sciences 22 (5) , 2616. 10.3390/ijms22052616

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Myotonic dystrophy type 1 (DM1) is the most complex and variable trinucleotide repeat disorder caused by an unstable CTG repeat expansion, reaching up to 4000 CTG in the most severe cases. The genetic and clinical variability of DM1 depend on the sex and age of the transmitting parent, but also on the CTG repeat number, presence of repeat interruptions and/or on the degree of somatic instability. Currently, it is difficult to simultaneously and accurately determine these contributing factors in DM1 patients due to the limitations of gold standard methods used in molecular diagnostics and research laboratories. Our study showed the efficiency of the latest PacBio long-read sequencing technology to sequence large CTG trinucleotides, detect multiple and single repeat interruptions and estimate the levels of somatic mosaicism in DM1 patients carrying complex CTG repeat expansions inaccessible to most methods. Using this innovative approach, we revealed the existence of de novo CCG interruptions associated with CTG stabilization/contraction across generations in a new DM1 family. We also demonstrated that our method is suitable to sequence the DM1 locus and measure somatic mosaicism in DM1 families carrying more than 1000 pure CTG repeats. Better characterization of expanded alleles in DM1 patients can significantly improve prognosis and genetic counseling, not only in DM1 but also for other tandem DNA repeat disorders.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// 4.0/).
Publisher: MDPI
ISSN: 1422-0067
Date of First Compliant Deposit: 22 March 2021
Date of Acceptance: 27 February 2021
Last Modified: 05 May 2023 01:58

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