Which diseases are associated with CTG (cytosine-thymine-guanine) trinucleotide repeats?

From the Guidelines

Myotonic dystrophy type 1 (DM1) is the most prominent disease associated with CTG trinucleotide repeats, with other conditions including Huntington disease-like 2 (HDL2), spinocerebellar ataxia type 8 (SCA8), and Fuchs endothelial corneal dystrophy (FECD) also linked to CTG repeat expansions. These diseases are characterized by the abnormal expansion of CTG repeats in specific genes, leading to toxic RNA gain-of-function and disruption of cellular function 1. The severity of symptoms in these diseases often correlates with the number of repeats, with larger expansions typically causing earlier onset and more severe disease manifestations, a phenomenon known as anticipation 1.

Key Diseases Associated with CTG Trinucleotide Repeats

• Myotonic dystrophy type 1 (DM1): caused by expansion of an unstable CTG trinucleotide repeat in the 3′ untranslated region of the DMPK gene 1
• Huntington disease-like 2 (HDL2): linked to CTG repeat expansions, although the specific genetic mechanism may differ from DM1
• Spinocerebellar ataxia type 8 (SCA8): associated with CTG repeat expansions, with a complex pattern of inheritance and variable penetrance
• Fuchs endothelial corneal dystrophy (FECD): linked to CTG repeat expansions, with a focus on the genetic and molecular mechanisms underlying the disease

Clinical Significance of CTG Repeat Expansions

The number of CTG repeats in DM1 is correlated with the severity of symptoms, with larger expansions typically causing earlier onset and more severe disease manifestations 1. The clinical significance of CTG repeat expansions can be summarized as follows:

• Normal: 5-34 repeats, no disease association
• Variable allele: 35-49 repeats, increased risk of CTG repeat expansion in the next generation
• Fully-variable allele/Mild disease: 50-100 repeats, consistent with a diagnosis of myotonic dystrophy type 1, with mild symptoms
• Fully-variable allele/Classic disease: ~100- ~1000 repeats, consistent with a diagnosis of myotonic dystrophy type 1, with classic symptoms
• Fully-variable allele/Congenital disease: 1000-6000 repeats, consistent with a diagnosis of myotonic dystrophy type 1, with congenital symptoms

Genotype-Phenotype Association

The correlation between CTG repeat size, age of onset, and clinical severity is significant, with larger expansions typically causing earlier onset and more severe disease manifestations 1. However, the assessment of genotype-phenotype correlation is complicated by dynamic somatic mosaicism of the CTG repeat, which is biased toward continuous expansion throughout the lifetime of an affected individual. Interruptions in DM1 alleles, such as CCG, CGG, CAG, or CTC, can act as cis-acting modifiers with a stabilizing effect on DMPK expansions and are prone to relatively stable intergenerational transmission or even contractions of DMPK expansions independent of the sex of the transmitting parent 1.

From the Research

Diseases Associated with CTG Trinucleotide Repeats

• Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease caused by a CTG triplet expansion in the 3'-untranslated region (3'-UTR) of the DMPK gene 2, 3, 4, 5.
• The CTG repeat expansion is thought to be mediated by a toxic RNA gain of function, leading to a progressive muscular dystrophy, myotonia, cataracts, cardiac arrhythmia, testicular atrophy, and insulin resistance 3, 5.
• The identification of variant expansions containing unstable CCG, CTC, and CGG interruptions within the DMPK alleles can lead to practical consequences in DM1 genetic counseling and testing, as these exams can give false negative results 2.
• The prognosis of the disease in patients with interrupted alleles is difficult to determine due to the great uncertainty about the genotype-phenotype correlations 2.
• Current attempts to develop therapy for DM1 mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA, but a DNA-directed strategy using CRISPR/Cas9 technology has shown promise in removing the repeat tract from normal and large expanded DMPK alleles 4.
• Replication inhibitors have been shown to modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells, suggesting a role for the perturbation of replication fork dynamics in DM1 CTG expansions 6.