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Article

Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles

by
Jan Radvanszky
1,2,3,*,
Michaela Hyblova
2,4,
Eva Radvanska
5,
Peter Spalek
6,
Alica Valachova
7,
Gabriela Magyarova
8,
Csaba Bognar
2,
Emil Polak
2,9,
Tomas Szemes
2,3,4 and
Ludevit Kadasi
1,2
1
Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
2
Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia
3
Comenius University Science Park, 841 04 Bratislava, Slovakia
4
Geneton s.r.o., 841 04 Bratislava, Slovakia
5
Department of Neonatology, Faculty Hospital Nove Zamky, 940 34 Nove Zamky, Slovakia
6
Centre for Neuromuscular Diseases, University Hospital Bratislava, 826 06 Bratislava, Slovakia
7
Department of Clinical Genetics, Faculty Hospital Trencin, 911 71 Trencin, Slovakia
8
Department of Laboratory Medicine, Faculty Hospital L Pasteur Kosice, 041 90 Kosice, Slovakia
9
Grow Cube s.r.o., 900 84 Igram, Slovakia
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(17), 3934; https://doi.org/10.3390/jcm10173934
Submission received: 7 July 2021 / Revised: 23 August 2021 / Accepted: 31 August 2021 / Published: 31 August 2021
(This article belongs to the Section Clinical Neurology)
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Abstract

Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguous CNBP alleles containing uninterrupted CCTG repeats in the range between 32 and 42 repeats. While these grey-zone alleles are most likely not pathogenic themselves, since other pathogenic mutations were identified and particular family structures did not support their pathogenic role, they were found to be unstable during intergenerational transmission. On the other hand, there was no observable general microsatellite instability in the genome of the carriers of these alleles. Our results further refine the division of CNBP CCTG repeat alleles into two major groups, i.e., interrupted and uninterrupted alleles. Both interrupted and uninterrupted alleles with up to approximately 30 CCTG repeats were shown to be generally stable during intergenerational transmission, while intergenerational as well as somatic instability seems to gradually increase in uninterrupted alleles with tract length growing above this threshold.
Keywords: cellular retroviral nucleic acid-binding protein; CNBP; DM2; expansion; myotonic dystrophy type 2; premutation cellular retroviral nucleic acid-binding protein; CNBP; DM2; expansion; myotonic dystrophy type 2; premutation

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MDPI and ACS Style

Radvanszky, J.; Hyblova, M.; Radvanska, E.; Spalek, P.; Valachova, A.; Magyarova, G.; Bognar, C.; Polak, E.; Szemes, T.; Kadasi, L. Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles. J. Clin. Med. 2021, 10, 3934. https://doi.org/10.3390/jcm10173934

AMA Style

Radvanszky J, Hyblova M, Radvanska E, Spalek P, Valachova A, Magyarova G, Bognar C, Polak E, Szemes T, Kadasi L. Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles. Journal of Clinical Medicine. 2021; 10(17):3934. https://doi.org/10.3390/jcm10173934

Chicago/Turabian Style

Radvanszky, Jan, Michaela Hyblova, Eva Radvanska, Peter Spalek, Alica Valachova, Gabriela Magyarova, Csaba Bognar, Emil Polak, Tomas Szemes, and Ludevit Kadasi. 2021. "Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles" Journal of Clinical Medicine 10, no. 17: 3934. https://doi.org/10.3390/jcm10173934

APA Style

Radvanszky, J., Hyblova, M., Radvanska, E., Spalek, P., Valachova, A., Magyarova, G., Bognar, C., Polak, E., Szemes, T., & Kadasi, L. (2021). Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles. Journal of Clinical Medicine, 10(17), 3934. https://doi.org/10.3390/jcm10173934

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