Surreal illustration of newborn with heart symbol and DNA strands, representing Tetralogy of Fallot research.

Decoding Tetralogy of Fallot: Can Newborn Blood Reveal the Secrets?

Mira Elwood in Health & Wellness December 2025 • 4 min read.

"Epigenetic clues in newborn blood offer a new path to early detection and understanding of Tetralogy of Fallot, a serious congenital heart defect."

Tetralogy of Fallot (TOF) is a complex congenital heart defect (CCHD) that affects newborns, characterized by a combination of four heart abnormalities. While the exact cause of TOF remains largely unknown, understanding the underlying mechanisms is crucial for improving diagnosis and treatment.

Early detection of TOF is vital for reducing complications and ensuring timely intervention. However, a significant number of cases are missed during prenatal screenings and in the newborn period. This highlights the urgent need for more accurate and reliable diagnostic tools.

Now, innovative research is diving into the world of epigenetics, exploring how variations in DNA methylation in newborn blood may hold the key to identifying TOF early on. This article explores these findings, offering insights into the potential of epigenetic markers in revolutionizing TOF detection and management.

Epigenetics: Unlocking TOF's Secrets in Newborn Blood

Surreal illustration of newborn with heart symbol and DNA strands, representing Tetralogy of Fallot research.

Researchers conducted a genome-wide methylation assay on newborn blood samples from 24 infants with non-syndromic TOF and 24 unaffected controls. The team used advanced technology to analyze DNA methylation patterns, pinpointing specific sites where methylation differed significantly between the two groups.

The study revealed 64 significantly differentially methylated CpG sites (locations on DNA where methylation occurs) in TOF cases. Of these, 25 CpG sites demonstrated high accuracy in predicting TOF, based on the area under the receiver operating characteristic curve (AUC ROC).

Key Finding: 51 CpG targets showed a methylation difference of ≥10% between TOF and controls, suggesting a strong biological significance.
Gene Ontology Analysis: Identified biological processes and functions related to differentially methylated genes, including CHD development, cardiomyopathy, diabetes, immunological processes, and inflammation.
Specific Genes: Multiple genes known or plausibly linked to heart development and postnatal heart disease were found to be differentially methylated in newborns with TOF, including ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9.

These findings suggest that variations in DNA methylation play a significant role in TOF development, offering potential new avenues for early detection and targeted therapies. The identification of specific genes and pathways involved also provides valuable insights into the underlying mechanisms of this complex heart defect.

A New Dawn for TOF Detection and Understanding

This research offers a promising step towards improving early detection and understanding of Tetralogy of Fallot. By identifying specific epigenetic markers in newborn blood, scientists are paving the way for more accurate and non-invasive diagnostic tools.

The insights gained into the genes and pathways involved in TOF development could also lead to the development of targeted therapies, addressing the underlying mechanisms of this complex heart defect.

While further research is needed to validate these findings and translate them into clinical applications, this study provides a compelling glimpse into the potential of epigenetics to revolutionize the diagnosis and treatment of congenital heart defects.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1371/journal.pone.0203893, Alternate LINK

Title: Newborn Blood Dna Epigenetic Variations And Signaling Pathway Genes Associated With Tetralogy Of Fallot (Tof)

Subject: Multidisciplinary

Journal: PLOS ONE

Publisher: Public Library of Science (PLoS)

Authors: Uppala Radhakrishna, Sangeetha Vishweswaraiah, Avinash M. Veerappa, Rita Zafra, Samet Albayrak, Prajna H. Sitharam, Nazia M. Saiyed, Nitish K. Mishra, Chittibabu Guda, Ray Bahado-Singh

Published: 2018-09-13

Everything You Need To Know

What is Tetralogy of Fallot, and how does newborn blood relate to it?

Tetralogy of Fallot (TOF) is a congenital heart defect involving a combination of four heart abnormalities. The recent research focuses on variations in DNA methylation patterns in newborn blood as potential indicators of TOF.

What specific findings regarding CpG sites were revealed in the newborn blood of infants with Tetralogy of Fallot?

The study identified 64 significantly differentially methylated CpG sites in newborns with Tetralogy of Fallot. Among these, 25 CpG sites exhibited high accuracy in predicting TOF based on the area under the receiver operating characteristic curve (AUC ROC). Furthermore, 51 CpG targets showed a methylation difference of ≥10% between TOF cases and controls.

What biological processes were identified through gene ontology analysis in relation to Tetralogy of Fallot, and what implications do they have?

The analysis highlighted several biological processes and functions related to differentially methylated genes, including congenital heart defect development, cardiomyopathy, diabetes, immunological processes, and inflammation. This suggests that Tetralogy of Fallot involves a complex interplay of various biological pathways beyond just heart development. Further research is needed to explore the connections with diabetes and inflammation.

Which specific genes were found to be differentially methylated in newborns with Tetralogy of Fallot, and what is their significance?

Specific genes such as ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9 were found to be differentially methylated in newborns with Tetralogy of Fallot. These genes are known or plausibly linked to heart development and postnatal heart disease. For example, RUNX genes are vital transcription factors involved in developmental processes. It is important to note that while these genes showed differences in methylation, this doesn't necessarily mean they are the only genes involved or that they are causal for Tetralogy of Fallot. Future research could focus on how changes in DNA methylation impacts transcription and gene expression.

How could the identification of epigenetic markers in newborn blood improve the detection and understanding of Tetralogy of Fallot?

The identification of epigenetic markers in newborn blood, specifically variations in DNA methylation at CpG sites related to genes like ABCB1 and RUNX, offers the potential for earlier and more accurate detection of Tetralogy of Fallot. This could lead to earlier interventions, improved outcomes, and a better understanding of the mechanisms underlying this complex heart defect. However, it's important to emphasize that epigenetic markers are only one aspect of TOF development and don't address the other possible factors such as genetics or environmental influences.