Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism

Abstract

Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.

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

“…Thus, interruption patterns can be conserved or vary upon transmission. Both situations have been previously described in interrupted families (Musova et al, 2009;Pešović et al, 2017;Tomé et al, 2018). Our CCG interruptions were found in blocks of two or three (in hexamers of CCGCTG that were repeated two or three times), and also as isolated cases.…”

“…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, ).…”

“…interruptions are thought to be related to a stabilization or even contraction of the pathological expansion (Braida et al, 2010;Cumming et al, 2018;Musova et al, 2009;Pešović et al, 2017;Tomé et al, 2018).…”

The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care

“…Other collaborative observational studies contributed to improve knowledge on myotonic stiffness in adults with DM1 [56], ophthalmologic defects [57], pyscho-cognitive aspects [58] and DM1 paediatric forms [59]. DM-scope registry also contributed to basic research by the identification of a unique interrupted genetic variant in two atypical DM1 pedigrees [60]. Finally, the DM-Scope registry was instrumental for the screening and recruitment of participants in interventional studies.…”