scholarly journals Repeat Interruptions Modify Age at Onset in Myotonic Dystrophy Type 1 by Stabilizing DMPK Expansions in Somatic Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Jovan Pešović ◽  
Stojan Perić ◽  
Miloš Brkušanin ◽  
Goran Brajušković ◽  
Vidosava Rakočević-Stojanović ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Age At Onset ◽  
Somatic Cells ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type

scholarly journals Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Dušanka Savić Pavićević ◽  
Jelena Miladinović ◽  
Miloš Brkušanin ◽  
Saša Šviković ◽  
Svetlana Djurica ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Molecular Genetics ◽  
Myotonic Dystrophy ◽  
Age At Onset ◽  
Gender Effect ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
Parental Gender

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of theDMPKgene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

scholarly journals Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

2019 ◽  
Author(s):  
Adam Kurkiewicz ◽  
Anneli Cooper ◽  
Emily McIlwaine ◽  
Sarah A. Cumming ◽  
Berit Adam ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Myotonic Dystrophy ◽  
Genetic Disorder ◽  
Age At Onset ◽  
Alternative Polyadenylation ◽  
Microarray Dataset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Statistical Framework

AbstractMyotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3’-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to trans-dysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.

scholarly journals Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

Neurology ◽  
2019 ◽  
Vol 93 (10) ◽  
pp. e995-e1009 ◽  
Author(s):  
Sarah A. Cumming ◽  
Cecilia Jimenez-Moreno ◽  
Kees Okkersen ◽  
Stephan Wenninger ◽  
Ferroudja Daidj ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Disease Severity ◽  
Target Identification ◽  
Age At Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Specific Outcome ◽  
Allele Length ◽  
Ctg Repeat

ObjectiveTo evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life—Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.MethodsWe used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.ResultsWe confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7–20.7, 2-tailed t test t = −3.7, p = 0.0019).ConclusionsCareful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.

scholarly journals Molecular and Clinical Implications of Variant Repeats in Myotonic Dystrophy Type 1

2021 ◽  
Vol 23 (1) ◽  
pp. 354
Author(s):  
Stojan Peric ◽  
Jovan Pesovic ◽  
Dusanka Savic-Pavicevic ◽  
Vidosava Rakocevic Stojanovic ◽  
Giovanni Meola
Keyword(s):  
Dna Methylation ◽  
Myotonic Dystrophy ◽  
Age At Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Structural Variations ◽  
Ctg Repeats ◽  
Monogenic Diseases ◽  
Additional Level

Myotonic dystrophy type 1 (DM1) is one of the most variable monogenic diseases at phenotypic, genetic, and epigenetic level. The disease is multi-systemic with the age at onset ranging from birth to late age. The underlying mutation is an unstable expansion of CTG repeats in the DMPK gene, varying in size from 50 to >1000 repeats. Generally, large expansions are associated with an earlier age at onset. Additionally, the most severe, congenital DM1 form is typically associated with local DNA methylation. Genetic variability of DM1 mutation is further increased by its structural variations due to presence of other repeats (e.g., CCG, CTC, CAG). These variant repeats or repeat interruptions seem to confer an additional level of epigenetic variability since local DNA methylation is frequently associated with variant CCG repeats independently of the expansion size. The effect of repeat interruptions on DM1 molecular pathogenesis is not investigated enough. Studies on patients indicate their stabilizing effect on DMPK expansions because no congenital cases were described in patients with repeat interruptions, and the age at onset is frequently later than expected. Here, we review the clinical relevance of repeat interruptions in DM1 and genetic and epigenetic characteristics of interrupted DMPK expansions based on patient studies.

SEVERE CONGENITAL MYOTONIC DYSTROPHY TYPE 1

2018 ◽  
Vol 97 (1) ◽  
pp. 78-81
Author(s):  
E.A. Mamaeva ◽  
◽  
L.A. Fedorova ◽  
S.E. Voronovich ◽  
V.D. Nazarov ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Congenital Myotonic Dystrophy
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