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Molecular genetic and clinical characterization of myotonic dystrophy type 1 patients carrying variant repeats within DMPK expansions
Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency o...
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Published in: | Neurogenetics 2017-12, Vol.18 (4), p.207-218 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the
DMPK
gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the
DMPK
expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products. PCR-based southern blot was performed to get insight into the intergenerational mutational dynamics of variant expanded alleles. All patients carrying variant repeats were clinically re-examined. Variant repeats were observed in eight patients from five families (2.9%). They were detected only at the 3′ end of
DMPK
expansions. CCG variant repeats were present in seven patients, either as a part of regular runs of CCGCTG hexamer, individual repeats, or CCG blocks. Analyses of three intergenerational transmissions revealed a considerable stability or likely a contraction of variant expanded alleles. Intriguingly, a decrease in age at onset accompanied these transmissions. Overall, patients were characterized by a milder phenotype and/or some atypical symptoms that could be rather clinically suggestive of myotonic dystrophy type 2. In addition, the first case of de novo CTC variant repeat was observed. Variant repeats might explain a part of the phenotypic variability in a small percent of DM1 patients and likely display a stabilizing effect on the meiotic instability of
DMPK
expanded alleles. |
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ISSN: | 1364-6745 1364-6753 |
DOI: | 10.1007/s10048-017-0523-7 |