250 CTG repeats in DMPK is a threshold for correlation of expansion size and age at onset of juvenile-adult DM1

Abstract

Myotonic dystrophy type 1 (DM1) is associated with an expansion of CTG repeats in the 3'UTR of the DMPK gene. It is accepted, as in other trinucleotide diseases, that the number of the repeats is correlated with age at onset and severity of the disease. However, assessment of genotype-phenotype correlation in DM1 is complicated with the expansion-biased somatic instability of mutant alleles over time and difficulties in precise assessment of the number of repeats by standard Southern blot hybridization. In order to clarify this issue we defined DM1 expansion size in lymphocytes by three parameters: size of progenitor, average, and largest allele, using a more precise small-pool/long-range PCR technique. We found a negative linear correlation of age at onset and average expansion size in juvenile-adult DM1 patients (35 out of 46) whose progenitor allele is less than 245 repeats long. Our result favors the hypothesis of the existence of a threshold in the progenitor allele size beyond which number of CTG repeats does not influence age at onset. Potential clinical significance is that the average allele size could be a useful indicator for the age at onset in juvenile-adult DM1 patients with relatively short progenitor allele. To test whether somatic instability of mutant alleles influences the progression of DM1, patients were divided in three phenotypic classes according to the severity of neuromuscular symptoms. We showed that the largest expansion in each DM1 phenotypic class reflects somatic instability of mutant allele over time independently of progenitor allele size and patient's age at sampling. The mean of the largest expansion was significantly different between phenotypic classes, implying the possible association between expansion-biased somatic instability of mutant alleles over time and progression of neuromuscular symptoms.

Epidemiological and Genetic Studies of Myotonic Dystrophy Type 1 in Taiwan

“…Genetic analysis of this DM1 pool indicates that clinical anticipation could occur in families with transmission contraction of CTG repeats. In agreement with previous reports [25,26], we also found that the correlation between age at onset and CTG repeat size is significant only for patients with small expansions. Finally, we present evidence for the somatic mosaicism of CTG repeat sizes in a premutation carrier.…”

“…However, our data favor the hypothesis that there exists an expansion size threshold at F250 repeats, beyond which the expansion size does not influence the onset age [25,26]. The contradictory observations could be attributed to differences in the recruitment of patient samples and the way the data were presented.…”

Molecular and Clinical Characteristics of Myotonic Dystrophy Type 1 in Koreans

“…The molecular tests diagnose patients with 100% accuracy, without overlap between normal alleles and expanded full penetrance alleles. In contrast, the clinical manifestations and their severity broadly correlate with the size of CTG repeat expansion [15][16][17], but findings vary greatly between patients.…”

Efficient and Highly Sensitive Screen for Myotonic Dystrophy Type 1 Using a One-Step Triplet-Primed PCR and Melting Curve Assay

“…Although large CTG repeat sizes have been correlated with early-onset DM1, there appears to be a threshold size beyond which the absolute repeat size in lymphocytes will no longer be a good indicator of age at onset in classic DM1 cases. 11,12 Hamshere et al 11 deduced that this threshold might range from 145 to 400 CTG repeats, whereas Savi c et al 12 reported a threshold value of 250 CTG repeats. Thus, repeat size may be a good predictor for age of onset in affected individuals carrying small expansions, but not in those carrying large expansions.…”

“…10 Although CTG repeat size information is potentially useful in predicting disease severity and age at onset, there appears to be no significant correlation between size and age at onset beyond a threshold repeat size, in particular for classic DM1. 11,12 Not only does DM1 exhibit phenotypic heterogeneity, it also shares some overlapping clinical features with myotonic dystrophy type 2 and other nondystrophic myotonias, which are genetically distinct disorders. 13,14 Molecular detection of the DMPK CTG repeat expansion is thus essential for definitive diagnosis of DM1.…”