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Table 3 Abnormal DNA methylation profiling in CHD

From: The role of DNA methylation in syndromic and non-syndromic congenital heart disease

Study (reference)

Study population Sample type

Cohort

Sample size

Methylation measures

DNA methylation change

[109]

Myocardial tissues (right ventricle/right atrium)

TOF: 8, VSD: 8

Case: 16, Control: 7

DNA methylation profiles were generated using MBD-seq

A significant overlap for hypermethylated promoters and down-regulated genes was found, and vice versa. A hypermethylated CpG island in the promoter of SCO2 was identified

[112]

Fetal heart tissue

6 DS without CHD, 6 DS with CHD, 6 isolated CHD

Case: 18, Control: 4

Global methylation profile was studied by using the Illumina Infinium Human Methylation27 array Platform

Hypermethylation of several intragenic sites at the MSX1 gene was found in iCHD Hypermethylation of the GATA4 gene was present in Down syndrome with or without congenital heart defects, as well as iCHD

[119]

Children (1 to 48 months), Myocardial tissues (right ventricle)

TOF

Case: 32, Control: 15

Sequenom MassARRAY platform was performed to examine the methylation levels of LINE-1, NKX2-5, HAND1 and TBX20

Lower LINE-1 methylation levels are associated with increased risk of TOF. Higher methylation levels of NKX2-5 and HAND1 and lower methylation levels of TBX20 were observed in TOF patients than in controls

[124]

New born (24 to 79 h), Blood

AVS

Case: 24, Control: 24

A genome-wide DNA methylation analysis using an Illumina Infinium 450 k human methylation assay was conducted

The study identified significantly-altered CpG methylation at 59 sites in 52 genes in AVS subjects as compared to controls, including DUSP27, RUNX1, TXNRD2, APOA5 and PCSK9

[125]

New born (24 to 79 h), Blood

TOF

Case: 24, Control: 24

Genome-wide methylation assay used Illumina Infinium HumanMethylation450 BeadChips

64 differentially methylated CpG sites in TOF cases were identified. Multiple differentially methylated genes are known or plausibly linked to heart development and postnatal heart disease

[133]

New born (24 to 72 h), Blood

DS patients with or without CHD

DS patients with CHD: 11, without CHD: 10

Low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA was performed to examine DNA methylation profiles

A comparation of DMRs between DS with and without CHD distinguished 1588 nominally significant DMRs (35% hypermethylated, 65% hypomethylated). There was hypomethylated DMR mapped to RUNX1 in CHD

[49]

Blood

DORV

Monozygotic twins, Case: 1, Control: 1

The DNA methylation pattern were analyzed using reduced representation bisulfite sequencing

Many DMR-related genes are enriched in pathways that contribute to cardiac development, such as ZIC3 and NR2F2

[139]

Blood

TOF

Monozygotic twins, Case: 2, Control: 2

Whole genome sequencing (WGS) and whole genome bisulfite sequencing (WGBS) were used to examine the genetic and epigenetic differences

Difference between the two monozygotic discordant twin pairs was observed in epigenetic alterations rather than at the genetic or structural genomic level, such as DMCs in the promoter region of the cardiac transcription factors TBX20, GATA4 and NKX2-5

[12]

Blood

HLHS: 8, VSD: 8, ASD: 12, CoA: 14, PS: 14, ToF: 14

Case: 60, Control: 32

Genome-wide DNA methylation analysis was performed on DNA from newborn blood spots

Profound differences in cytosine methylation were observed in hundreds of genes in newborns with different types of CHD

[156]

Fetal skin fibroblasts

DS with CHD (VSD, ASD)

DS MZ twins discordant for CHD, Case: 4, Control: 4

Reduced Representation Bisulphite Sequencing (RRBS) were applied to profile DNA methylation changes

197 DMRs in monozygotic twins discordant for VSD and 88 DMRs in monozygotic twins discordant for AVSD were identified, including 13 common DMRs between two sets

[141]

Placenta

VSD

Case: 8, Control: 10

Genome-wide DNA methylation assay was performed using the Illumina HumanMethylation450 BeadChip assay

Most differentially methylated genes, have been shown to be associated with heart development or disease

[142]

Placenta

TOF

Case: 8, Control: 10

The Illumina Infinium HumanMethylation450 BeadChip assay was used

ARHGAP22, CDK5, TRIM27 and IER3 had outstanding predictive accuracy for the prediction of TOF. ID4, HES7 and PPP3CA, which may be associated with heart disease, also showed differential methylation in this research

[116]

Myocardium

TDF, VSD, DCRV

Case: 24, Control: 11

The methylation of a BRG1 promoter was analyzed using pyrosequencing and the MassARRAY platform

BRG1

hypomethylation

[149]

Myocardial tissues

CHD

Case: 31, Control: 2

BSP and MSP were used to detect the methylation in CITED2 promoter region

CITED2

hypermethylation

[143]

Blood

VSD, ASD, TOF, PDA, CoA, other CHDs

Case: 27, Control: 28

Eighteen imprinted genes methylation were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

GRB10, MEST

hypermethylation

PEG10, NAP1L5, INPP5F, PLAGL1, NESP, MEG3

hypomethylation

[144]

Blood

CHD with EM

Case: 24, Control: 20

The methylation levels of 3 candidate genes were analysed by the MassARRAY platform

SNRPN, ZAC1

hypermethylation

INPP5F

hypomethylation

[118]

Blood

AVSD, VSD

Case: 7, Control: 9

Methylation analysis of the promoter regions was performed by means of the Human Promoter 1.0 Arrays (Affymetrix)

NRG1

hypermethylation