De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3'-untranslated region of the DMPK gene. The repeat expansion is somatically unstable and tends to increase in length with time, contributing to disease progression. In some individuals, the repeat array is interrupted by variant repeats such as CCG and CGG, stabilising the expansion and often leading to milder symptoms. We have characterised three families, each including one person with variant repeats that had arisen de novo on paternal transmission of the repeat expansion. Two individuals were identified for screening due to an unusual result in the laboratory diagnostic test, and the third due to exceptionally mild symptoms. The presence of variant repeats in all three expanded alleles was confirmed by restriction digestion of small pool PCR products, and allele structures were determined by PacBio sequencing. Each was different, but all contained CCG repeats close to the 3'-end of the repeat expansion. All other family members had inherited pure CTG repeats. The variant repeat-containing alleles were more stable in the blood than pure alleles of similar length, which may in part account for the mild symptoms observed in all three individuals. This emphasises the importance of somatic instability as a disease mechanism in DM1. Further, since patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and for patient stratification in DM1 clinical trials.

A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype

“…In the rest of intergenerational transmissions reported, and in the case of our patients P2 and P4, anticipation could not be assessed since patients in the next generation are still asymptomatic. The explanation for these findings is not apparent, since anticipation is not expected in these families; indeed, interruptions are thought to be related to a stabilization or even contraction of the pathological expansion (Braida et al, ; Cumming et al, ; Musova et al, ; Pešović et al, ; Tomé et al, ). However, anticipation was found in our studied intergenerational transmission, with this finding being also reported in other interrupted DM1 patients based on reported age of onset (Table ).…”

“…We detected the contraction of the expansion between patients P2 and P4, but expansion between patients P3 and P5. Previous studies suggest that CTG expansion containing variant repeat patterns display more frequently stable, or even contracted, DMPK alleles instead of further expanded DMPK alleles (Cumming et al, ; Musova et al, ; Pešović et al, ; Tomé et al, ). However, some studies have also found the expansion of the interrupted alleles from one generation to the other (Braida et al, ; Cumming et al, ; Pešović et al, ).…”

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

“…Interestingly, this mutational mechanism has previously been suggested in the origin of pure repetitive stretches of (CCG) n in the middle of the expanded (CTG) n , in DM1. The CCG interruptions may appear individually, in runs of CCGCTG or in a continuously block (Braida et al., ; Cumming et al., ; Pešović et al., ). The CCG blocks may be as large as 40 repeat units (Pešović et al., ).…”

“…It is unlikely that these large pure (ATTTT) n alleles with haplotype VIII have been originated by an (ATTTC) n deletion, because (1) ATTTC repeat contractions have never been detected in 22 parent-to-offspring transmissions (Corral-Juan et al, 2018;Seixas et al, 2017) and (2) Interestingly, this mutational mechanism has previously been suggested in the origin of pure repetitive stretches of (CCG) n in the middle of the expanded (CTG) n , in DM1. The CCG interruptions may appear individually, in runs of CCGCTG or in a continuously block (Braida et al, 2010;Cumming et al, 2018;Pešović et al, 2017). The CCG blocks may be as large as 40 repeat units (Pešović et al, 2017).…”

“…The CCG blocks may be as large as 40 repeat units (Pešović et al, 2017). It was suggested that CCG blocks originate, first, by base substitution (T>C) followed by small changes in length, which later results in longer runs of CCGs (Braida et al, 2010;Cumming et al, 2018). (Ewing et al, 2013).…”