Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing
Myotonic dystrophy type 1 (DM1) is a serious multisystem disorder caused by GCA repeat expansions in the DMPK gene. Early and accurate diagnosis, often requiring reliable DNA-diagnostic techniques, is critical for preventing life-threatening cardiac complications. Clinically, two main diagnostic cha...
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Elsevier
2025-02-01
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| Series: | Molecular and Cellular Probes |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0890850824000574 |
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| author | Ingrid Lojova Marcel Kucharik Zuzana Pös Andrej Balaz Andrea Zatkova Eva Tothova Tarova Jaroslav Budis Ludevit Kadasi Tomas Szemes Jan Radvanszky |
| author_facet | Ingrid Lojova Marcel Kucharik Zuzana Pös Andrej Balaz Andrea Zatkova Eva Tothova Tarova Jaroslav Budis Ludevit Kadasi Tomas Szemes Jan Radvanszky |
| author_sort | Ingrid Lojova |
| collection | DOAJ |
| description | Myotonic dystrophy type 1 (DM1) is a serious multisystem disorder caused by GCA repeat expansions in the DMPK gene. Early and accurate diagnosis, often requiring reliable DNA-diagnostic techniques, is critical for preventing life-threatening cardiac complications. Clinically, two main diagnostic challenges exist. Firstly, because of overlapping symptomatology with other conditions, conventional DNA-testing methods focusing on DM1 expansion detection ensure diagnostic results only in a small subset of patients, and frequently, further DNA-testing in remaining cases is necessary. Secondly, because of variable symptomatology and age of onset, not all DM1 patients are referred for DM1 genetic testing, leading to unrecognized but at-risk cases. When using conventional methods, the main technical problems are expanded-allele sizing and sensitivity to the presence of sequence interruptions. On a set of 50 individual genomes, including ten DM1 patients, we tested the performance of short-read whole-genome sequencing (WGS), one of the most up-to-date molecular testing methods. We identified all expansion-range DM1 alleles and characterized sequence interruptions in seven expansion-range/premutation-range alleles. Although neither the tested conventional methods, nor WGS allowed expanded-allele sizing, conventional methods provided higher sizing limits for normal-range alleles. Genotyping concordance rate was found to be 95–99 %. WGS was found to be superior in elucidating the sequence structure of the motifs, even if they fall outside the sizing limit (from partial reads). In addition, WGS enables the identification of genetic modifiers in other genes and the detection of alternative diagnoses in DM1-negative patients by extension of the bioinformatic evaluation of the generated data. |
| format | Article |
| id | doaj-art-fee6c6affefb4e47b519fff932526a46 |
| institution | DOAJ |
| issn | 0890-8508 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular and Cellular Probes |
| spelling | doaj-art-fee6c6affefb4e47b519fff932526a462025-08-20T03:12:40ZengElsevierMolecular and Cellular Probes0890-85082025-02-017910200510.1016/j.mcp.2024.102005Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencingIngrid Lojova0Marcel Kucharik1Zuzana Pös2Andrej Balaz3Andrea Zatkova4Eva Tothova Tarova5Jaroslav Budis6Ludevit Kadasi7Tomas Szemes8Jan Radvanszky9Institute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Comenius University Science Park, Bratislava, Slovakia; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Comenius University Science Park, Bratislava, Slovakia; Geneton Ltd., Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Geneton Ltd., Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Geneton Ltd., Bratislava, Slovakia; Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Department of Biology, Faculty of Education, J. Selye University, Komárno, SlovakiaComenius University Science Park, Bratislava, Slovakia; Geneton Ltd., Bratislava, Slovakia; Genovisio Ltd., Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, SlovakiaComenius University Science Park, Bratislava, Slovakia; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia; Geneton Ltd., Bratislava, SlovakiaInstitute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia; Comenius University Science Park, Bratislava, Slovakia; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia; G2 Consulting Slovakia Ltd., Slovakia; Corresponding author. Institute of Clinical and Translational Research, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.Myotonic dystrophy type 1 (DM1) is a serious multisystem disorder caused by GCA repeat expansions in the DMPK gene. Early and accurate diagnosis, often requiring reliable DNA-diagnostic techniques, is critical for preventing life-threatening cardiac complications. Clinically, two main diagnostic challenges exist. Firstly, because of overlapping symptomatology with other conditions, conventional DNA-testing methods focusing on DM1 expansion detection ensure diagnostic results only in a small subset of patients, and frequently, further DNA-testing in remaining cases is necessary. Secondly, because of variable symptomatology and age of onset, not all DM1 patients are referred for DM1 genetic testing, leading to unrecognized but at-risk cases. When using conventional methods, the main technical problems are expanded-allele sizing and sensitivity to the presence of sequence interruptions. On a set of 50 individual genomes, including ten DM1 patients, we tested the performance of short-read whole-genome sequencing (WGS), one of the most up-to-date molecular testing methods. We identified all expansion-range DM1 alleles and characterized sequence interruptions in seven expansion-range/premutation-range alleles. Although neither the tested conventional methods, nor WGS allowed expanded-allele sizing, conventional methods provided higher sizing limits for normal-range alleles. Genotyping concordance rate was found to be 95–99 %. WGS was found to be superior in elucidating the sequence structure of the motifs, even if they fall outside the sizing limit (from partial reads). In addition, WGS enables the identification of genetic modifiers in other genes and the detection of alternative diagnoses in DM1-negative patients by extension of the bioinformatic evaluation of the generated data.http://www.sciencedirect.com/science/article/pii/S0890850824000574Massively parallel sequencingMyotonic dystrophy type 1Repeat expansion disordersTandem repeatsWhole genome sequencing |
| spellingShingle | Ingrid Lojova Marcel Kucharik Zuzana Pös Andrej Balaz Andrea Zatkova Eva Tothova Tarova Jaroslav Budis Ludevit Kadasi Tomas Szemes Jan Radvanszky Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing Molecular and Cellular Probes Massively parallel sequencing Myotonic dystrophy type 1 Repeat expansion disorders Tandem repeats Whole genome sequencing |
| title | Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing |
| title_full | Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing |
| title_fullStr | Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing |
| title_full_unstemmed | Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing |
| title_short | Advancing molecular diagnostics of myotonic dystrophy type 1 using short-read whole genome sequencing |
| title_sort | advancing molecular diagnostics of myotonic dystrophy type 1 using short read whole genome sequencing |
| topic | Massively parallel sequencing Myotonic dystrophy type 1 Repeat expansion disorders Tandem repeats Whole genome sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S0890850824000574 |
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