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Article

Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1

1
Centre de Recherche en Myologie, Inserm, Institut de Myologie, Sorbonne Université, F-75013 Paris, France
2
Dementia Research Institute, Cardiff University, Cardiff CF10 3AT, UK
3
Pacific Biosciences, Menlo Park, CA 94025, USA
4
Genetics Department of the Hospital of Toulouse, F-31059 Toulouse, France
5
CHU de Nantes, Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, F-44000 Nantes, France
6
CHU Nantes, Service de Génétique Médicale, Centre de Référence des Maladies Neuromusculaires AOC, F-44000 Nantes, France
*
Author to whom correspondence should be addressed.
Academic Editor: Irmgard Tegeder
Int. J. Mol. Sci. 2021, 22(5), 2616; https://doi.org/10.3390/ijms22052616
Received: 12 February 2021 / Revised: 26 February 2021 / Accepted: 27 February 2021 / Published: 5 March 2021
(This article belongs to the Collection Feature Papers in Molecular Biology)
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. View Full-Text
Keywords: myotonic dystrophy type 1; long read sequencing; somatic mosaicism; interrupted CTG repeat expansion myotonic dystrophy type 1; long read sequencing; somatic mosaicism; interrupted CTG repeat expansion
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MDPI and ACS Style

Mangin, A.; de Pontual, L.; Tsai, Y.-C.; Monteil, L.; Nizon, M.; Boisseau, P.; Mercier, S.; Ziegle, J.; Harting, J.; Heiner, C.; Gourdon, G.; Tomé, S. Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1. Int. J. Mol. Sci. 2021, 22, 2616. https://doi.org/10.3390/ijms22052616

AMA Style

Mangin A, de Pontual L, Tsai Y-C, Monteil L, Nizon M, Boisseau P, Mercier S, Ziegle J, Harting J, Heiner C, Gourdon G, Tomé S. Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1. International Journal of Molecular Sciences. 2021; 22(5):2616. https://doi.org/10.3390/ijms22052616

Chicago/Turabian Style

Mangin, Antoine, Laure de Pontual, Yu-Chih Tsai, Laetitia Monteil, Mathilde Nizon, Pierre Boisseau, Sandra Mercier, Janet Ziegle, John Harting, Cheryl Heiner, Geneviève Gourdon, and Stéphanie Tomé. 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, no. 5: 2616. https://doi.org/10.3390/ijms22052616

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