Myotonic dystrophy type 1 (DM1) clinical subtypes and CTCF site methylation status flanking the CTG expansion are mutant allele length-dependent

Fernando Morales, Eyleen Corrales, Baili Zhang, Melissa Vásquez, Carolina Santamaría-Ulloa, Hazel Quesada, Mario Sirito, Marcos R. Estecio, Darren G. Monckton, Ralf Krahe

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Myotonic dystrophy type 1 (DM1) is a complex disease with a wide spectrum of symptoms. The exact relationship between mutant CTG repeat expansion size and clinical outcome remains unclear. DM1 congenital patients (CDM) inherit the largest expanded alleles, which are associated with abnormal and increased DNA methylation flanking the CTG repeat. However, DNA methylation at the DMPK locus remains understudied. Its relationship to DM1 clinical subtypes, expansion size and age-at-onset is not yet completely understood. Using pyrosequencing-based methylation analysis on 225 blood DNA samples from Costa Rican DM1 patients, we determined that the size of the estimated progenitor allele length (ePAL) is not only a good discriminator between CDM and non-CDM cases (with an estimated threshold at 653 CTG repeats), but also for all DM1 clinical subtypes. Secondly, increased methylation at both CTCF sites upstream and downstream of the expansion was almost exclusively present in CDM cases. Thirdly, levels of abnormal methylation were associated with clinical subtype, age and ePAL, with strong correlations between these variables. Fourthly, both ePAL and the intergenerational expansion size were significantly associated with methylation status. Finally, methylation status was associated with ePAL and maternal inheritance, with almost exclusively maternal transmission of CDM. In conclusion, increased DNA methylation at the CTCF sites flanking the DM1 expansion could be linked to ePAL, and both increased methylation and the ePAL could be considered biomarkers for the CDM phenotype.

Original languageEnglish (US)
Pages (from-to)262-274
Number of pages13
JournalHuman molecular genetics
Volume31
Issue number2
DOIs
StatePublished - Jan 15 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

MD Anderson CCSG core facilities

  • Epigenomics Profiling Core Facility

Fingerprint

Dive into the research topics of 'Myotonic dystrophy type 1 (DM1) clinical subtypes and CTCF site methylation status flanking the CTG expansion are mutant allele length-dependent'. Together they form a unique fingerprint.

Cite this