Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

Abstract

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 the DMPK gene, 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.

Molecular Testing for Fragile X: Analysis of 5062 Tests from 1105 Fragile X Families—Performed in 12 Clinical Laboratories in Spain

“…They have also been observed in maternal transmissions of CAG repeats in Huntington disease, with a tendency for expansion in male offspring and contractions in female offspring [32]. In myotonic dystrophy although contractions of the CTG repeats are much less frequent than expansions, they are more frequently transmitted by males [33]. In our study, contractions also occur in maternal transmissions but only in a 2.6% of them, with no differences between male and female offsprings.…”

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…In DM, expansion length correlates roughly with disease severity (Brook et al 1992), although there is no apparent relationship between expansion length and the severity of splicing defects (Nakamori et al 2013). However, confidence in such relationships is complicated by somatic instability of repeat length (Savic Pavicevic et al 2013). Establishing the significance of such correlations will depend on the development of simpler, more accurate methods for measuring repeat length (Yum et al 2017).…”

Fuchs Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy

“…This observation may also be due to the phenomenon of anticipation, which has been documented in DM1 pedigrees as well as in many other trinucleotide repeat disorders. 12 Further investigation into the number of repeats in DM patients with concurrent FECD may provide some answers regarding whether or not there is a threshold repeat length for disease association.…”