Epigenetic markers for newborn congenital heart defect (CHD)

Bahado‐Singh, Ray O.; Zaffra, Rita; Albayarak, Samet; Chelliah, Anushka; Bolinjkar, Rashmi; Türkoğlu, Onur; Radhakrishna, Uppala

doi:10.3109/14767058.2015.1069811

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…Зарегистрированы множественные случаи иНКЛЖ при серповидноклеточной анемии [14,16], беременности [17], нейромышечной патологии [12] и ХПН [13]. Эти наблюдения расширяют спектр этиопатогенетических гипотез от патологии эмбриогенеза к адаптивным патогенетическим механизмам, включающим компенсаторные изменения сердца в неблагоприятных условиях гемодинамической перегрузки и другие эпигенетические факторы [42]. 7.…”

Section: вариабельность нкмunclassified

Left ventricular noncompaction: a distinct cardiomyopathy or a composite anatomical syndrome?

Vaikhanskaya¹,

Sivitskaya

Курушко³

et al. 2018

Kardiologiia

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Left ventricular non-compaction (LVNC) is characterized by hypertrabecularity (thickened non-compact layer) with deep intertrabecular recesses that are continuous with the ventricle cavity, and a thin compact layer. The phenotypes of LVNС are extremely variable: the left or right ventricular variant, biventricular form, LVNC with symptoms of heart failure or arrhythmia, asymptomatic forms or variants with thromboembolic events. In 30–50 % of patients with LVNC genetic mutations of genes encoding sarcomeric or cytoskeletal proteins are revealed by a genetic study. The article presents a literature review on the problems of diagnosis, visualization, pathogenesis, variability of clinical manifestations of LVNC and its genetic heterogeneity. Clinical cases demonstrating LVNC as a concomitant anatomical syndrome due to monogenic Danone disease, as well as the family cardiomyopathy with the digenic inheritance of two phenotypes (LVNC with DCM) and the unique case of peripartum evolution of the acquired LVNC syndrome, all these cases are reflect the current uncertainty regarding to the pathogenesis and significance of LVNC. The main question is whether LVNC is a distinct cardiomyopathy or a morphologic trait and a composite anatomical syndrome of congenital heart disease or other cardiomyopathies (DCM, HCM, ARVC) remains controversial. Achievement of professional consensus guidelines about unification of diagnostic criteria and risk-stratification of LVNC, improvement of visualization tools and expansion of genetic testing will help to significantly expand our knowledge and understanding of the pathogenesis, clinical significance and prognosis of LVNC for optimization of the treatment strategy

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Section: вариабельность нкмunclassified

Left ventricular noncompaction: a distinct cardiomyopathy or a composite anatomical syndrome?

Vaikhanskaya¹,

Sivitskaya

Курушко³

et al. 2018

Kardiologiia

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“…Multiple prior studies have reported genome-wide DNA methylation profiles from archived dried blood spots using Infinium HumanMethylation450 BeadChips. [ 20 ] [ 21 ]. The Infinium HumanMethylation450 BeadChips array for methylation (Illumina, Inc., California, USA) contains >485,000 CpGs per sample in enhancer regions, coding regions, promoters and CpG islands at a single-nucleotide resolution and requires only 500 ng of genomic DNA per assay.…”

Section: Methodsmentioning

confidence: 99%

“…Epigenetic changes are largely tissue specific and the inaccessibility of the heart in living subjects is a monumental challenge to studying cardiac development in general. Work by our group [ 20 , 21 ] and others [ 22 ] have reported evidence that a significant minority of epigenetic marks in blood DNA mirror similar changes in inaccessible organs such as the heart and the brain respectively. This opens the possibility of ongoing epigenetic analysis of such organs.…”

Section: Introductionmentioning

confidence: 99%

Newborn blood DNA epigenetic variations and signaling pathway genes associated with Tetralogy of Fallot (TOF)

et al. 2018

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Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.

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“…Given the clinical significance of CHD and the frequency of missed or late diagnosis, this is a major deficiency. In our prior pilot data [17, 18] cytosine methylation status of blood leucocytes was found to be a potentially useful molecular biomarker for the detection of multiple different categories of CHD. This is consistent with the previously referenced attempts to use epigenetic signatures in leucocytes to detect psychiatric disorders [16].…”

Section: Introductionmentioning

confidence: 99%

“…We therefore reasoned that although not identical, there was likely to be a significant minority of cytosine loci in which parallel epigenetic modifications could be demonstrated in cardiac development genes in general and genes related to ventricular development in the placenta from VSD pregnancies. We had previously demonstrated this phenomenon in multiple categories of CHD using blood (leucocyte) from affected newborns as the surrogate tissue for detecting CHD [17, 18]. Our objective therefore in this proof of concept study was to evaluate the utility of cytosine methylation in placental DNA to elucidate the pathogenesis of and for the detection of isolated non-syndromic VSD.…”

Section: Introductionmentioning

confidence: 99%

Placental epigenetics for evaluation of fetal congenital heart defects: Ventricular septal defect (VSD)

Bahado‐Singh

Albayrak

Zafra

et al. 2018

Preprint

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Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue and is a potentially useful surrogate for the evaluation of fetal organ development. To understand epigenetic mechanisms that may play a role in the development of VSD, a genome-wide DNA methylation assay of the placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 normal controls was performed using the Illumina HumanMethylation450 BeadChip assay. The study identified a total of 80 highly accurate potential epigenomic markers in 80 genes for the detection of VSD; area under the receiver operating characteristic curve (AUC ROC) = 1.0 with significant 95% CI (FDR) p-values < 0.05. The biological processes and functions for these differentially methylated genes are known to be associated with heart development or heart disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). The study also identified eight microRNA genes that have the potential to be biomarkers for the early detection of VSD including miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting CHD.

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Epigenetic markers for newborn congenital heart defect (CHD)

Abstract: Profound differences in cytosine methylation were observed in hundreds of genes in newborns with different types of CHD. There appears to be the potential for development of accurate genetic biomarkers for CHD detection in newborns.

Cited by 15 publications

References 33 publications

Left ventricular noncompaction: a distinct cardiomyopathy or a composite anatomical syndrome?

Left ventricular noncompaction: a distinct cardiomyopathy or a composite anatomical syndrome?

Newborn blood DNA epigenetic variations and signaling pathway genes associated with Tetralogy of Fallot (TOF)

Placental epigenetics for evaluation of fetal congenital heart defects: Ventricular septal defect (VSD)

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