Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy

Genet Med. 2019 Nov;21(11):2453-2461. doi: 10.1038/s41436-019-0516-z. Epub 2019 Apr 17.


Purpose: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis.

Methods: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites.

Results: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs).

Conclusions: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.

Keywords: allele-specific methylation; bisulfite sequencing; diabetic embryopathy; infant of a diabetic mother; teratogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Biomarkers
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Diabetes Complications / genetics
  • Diabetes Mellitus / embryology*
  • Diabetes Mellitus / genetics
  • Female
  • Fetal Diseases / genetics*
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Infant, Newborn
  • Polymorphism, Single Nucleotide / genetics
  • Pregnancy
  • Quantitative Trait Loci / genetics


  • Biomarkers