Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy

Katharina V. Schulze, Amit Bhatt, Mahshid S. Azamian, Nathan C. Sundgren, Gladys E. Zapata, Patricia Hernandez, Karin Fox, Jeffrey R. Kaiser, John W. Belmont, Neil A. Hanchard

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StatePublished - Jan 1 2019

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Fetal Diseases
DNA Methylation
Biomarkers
Methylation
Alleles
Genes
Teratogens
Maternal Exposure
Quantitative Trait Loci
Embryonic Development
Nucleotides
Mothers
Newborn Infant
Phenotype

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)

Cite this

Schulze, K. V., Bhatt, A., Azamian, M. S., Sundgren, N. C., Zapata, G. E., Hernandez, P., ... 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
Schulze, Katharina V. ; Bhatt, Amit ; Azamian, Mahshid S. ; Sundgren, Nathan C. ; Zapata, Gladys E. ; Hernandez, Patricia ; Fox, Karin ; Kaiser, Jeffrey R. ; Belmont, John W. ; Hanchard, Neil A. / Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. In: Genetics in Medicine. 2019.
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abstract = "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.",
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Schulze, KV, Bhatt, A, Azamian, MS, Sundgren, NC, Zapata, GE, Hernandez, P, Fox, K, Kaiser, JR, Belmont, JW & Hanchard, NA 2019, 'Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy', Genetics in Medicine. https://doi.org/10.1038/s41436-019-0516-z

Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. / Schulze, Katharina V.; Bhatt, Amit; Azamian, Mahshid S.; Sundgren, Nathan C.; Zapata, Gladys E.; Hernandez, Patricia; Fox, Karin; Kaiser, Jeffrey R.; Belmont, John W.; Hanchard, Neil A.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy

AU - Schulze, Katharina V.

AU - Bhatt, Amit

AU - Azamian, Mahshid S.

AU - Sundgren, Nathan C.

AU - Zapata, Gladys E.

AU - Hernandez, Patricia

AU - Fox, Karin

AU - Kaiser, Jeffrey R.

AU - Belmont, John W.

AU - Hanchard, Neil A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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Schulze KV, Bhatt A, Azamian MS, Sundgren NC, Zapata GE, Hernandez P et al. Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. Genetics in Medicine. 2019 Jan 1. https://doi.org/10.1038/s41436-019-0516-z