DM1 Phenotype Modified by Repeat Interruptions

Published on Tue, 08/14/2018

Impact of “Pure” versus Variant Expanded Repeats in DM1

A key driving factor behind DM1 is the instability of expanded CTG repeats in DMPK, resulting in both germline and somatic expansions in repeat length that, in turn, reduce age of symptom onset and increase disease severity. Prior studies have noted that 3-5% of DM1 patients have their expanded CTG repeats interrupted by short runs of CCG, CTC or GGC repeats. Such allelic variants may impact genetics-based diagnostic methodologies, repeat stability, and DM1 phenotype.

Analysis of Variant Repeats in a Scottish Cohort

Drs. Sarah Cumming and Mark Hamilton (University of Glasgow and Queen Elizabeth University Hospital--Glasgow) and colleagues recruited and evaluated 251 adult DM1 subjects from four major clinical genetics centers to assess for the presence and impact of variant-containing CTG expansions that exceeded the normally pathogenic length threshold. Since they found that more common technologies were inadequate to detect allelic variants, research subject allelic structures were determined using the PacBio RS II sequencing platform.

The research team identified three DM1 families each with one individual with prior genetic diagnosis of DM1 that was then subjected to variant screening. Phenotypically, each had either no muscle signs or only mild signs of the disease (note: each had their genetic evaluation based upon familial history, not symptoms). Each was found to have paternally-transmitted, de novo CCG repeats near the 3’ end of their expanded CTG tracts. When comparing these three subjects to symptomatic DM1 subjects with similar estimated progenitor allele lengths, the team observed less somatic expansion in blood samples from those with variants. Returning to the full Scottish cohort for variant repeat sequencing, 18 total subjects were identified with variant-containing CTG expansions in DMPK.

Criticality of Understanding DM1 Allelic Variants

Since estimated progenitor allele length was similar between those with CCG repeat variants and patients with earlier onset/more severe DM1, these data lend further support for the argument that somatic expansion plays a vital role in the pathogenesis of DM1.

Genotypic modifiers have been implicated in phenotypic variations in neuromuscular diseases. Their impact can alter dramatically alter disease progression—e.g., LTBP4 and SPP1 variants alter muscle strength and ambulation in DMD—and thus is critical to understand for genetic counseling and clinical trials design. In the case of these findings from the Glasgow team, it is a sequence disruption in the disease-causing CTG repeat expansion that acts as the modifier, serving to mechanistically interfere with somatic cell repeat expansion. Although definitive conclusions are not provided by their data set, the investigators noted that germline transmission also may be significantly different in subjects with variant-containing CTG repeat expansions.

Finally, with the advent of new genomic technologies (including genome editing), knowledge of mechanisms underlying phenotypic differences between patients with “pure” versus variant expanded repeats may yield insights into novel drug discovery and development strategies for DM1.


De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1.
Cumming SA, Hamilton MJ, Robb Y, Gregory H, McWilliam C, Cooper A, Adam B, McGhie J, Hamilton G, Herzyk P, Tschannen MR, Worthey E, Petty R, Ballantyne B; Scottish Myotonic Dystrophy Consortium, Warner J, Farrugia ME, Longman C, Monckton DG.
Eur J Hum Genet. 2018 Jul 2. doi: 10.1038/s41431-018-0156-9. [Epub ahead of print]