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Title: Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy

Author
item SCHULZE, KATHARINA - Children'S Nutrition Research Center (CNRC)
item BHATT, AMIT - Baylor College Of Medicine
item AZAMIAN, MAHSHID - Baylor College Of Medicine
item SUNDGREN, NATHAN - Baylor College Of Medicine
item ZAPATA, GLADYS - Children'S Nutrition Research Center (CNRC)
item HERNANDEZ, PATRICIA - Children'S Nutrition Research Center (CNRC)
item FOX, KARIN - Baylor College Of Medicine
item KAISER, JEFFREY - Baylor College Of Medicine
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)
item HANCHARD, NEIL - Children'S Nutrition Research Center (CNRC)

Submitted to: Genetics in Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2019
Publication Date: 4/17/2019
Citation: Schulze, K.V., Bhatt, A., Azamian, M.S., Sundgren, N.C., Zapata, G.E., Hernandez, P., Fox, K., Kaiser, J.R., Belmont, J.W., Hanchard, N.A. 2019. Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. Genetics in Medicine. https://doi.org/10.1038/s41436-019-0516-z
DOI: https://doi.org/10.1038/s41436-019-0516-z

Interpretive Summary: Children born to mothers who had diabetes while pregnant are at an increased risk of having birth defects. The precise way this happens is still uncertain, and at present, there is no diagnostic test that can distinguish between birth defects resulting from diabetes exposure and birth defects from genetic or other causes. To investigate possible contributors to this observation, we assessed the level of chemical modification of DNA (known as DNA methylation) at millions of sites across the genome; this modification is known to regulate gene activity. We found that at some DNA sites, there were large and highly significant differences in methylation between diabetes-exposed infants with birth defects and infants without birth defects (both exposed and unexposed). Further, using methylation levels at specific sites in the genome, we were able to identify a unique pattern of methylation that could distinguish diabetes-exposed infants with birth defects from healthy infants (unexposed or exposed), and from infants with other causes of their birth defects (such as down syndrome). Our results demonstrate the strong link between nutritional stressors like diabetes and DNA methylation, and offer the possibility that methylation patterns could be used to provide a diagnosis for infants affected by maternal diabetes in utero.

Technical Abstract: 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. 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. 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). 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.