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Genetic advances in sporadic tetralogy of Fallot: discovery of novel HAND1 promoter variants

Pediatric Research volume 97, pages 1770–1771 (2025)Cite this article

One of the most common forms of congenital heart disease is Tetralogy of Fallot (TOF). The global birth prevalence of TOF is 3.3–3.9 per 100,000 live births.1 TOF is accompanied by a tetrad of anomalies, which include a ventricular septal defect (VSD), pulmonary stenosis, an aorta that overrides the ventricular septum, and right ventricular hypertrophy.2 The diagnosis of TOF can be made prenatally, usually discovered on an anatomy ultrasound. TOF may also be discovered postnatally in a neonate who presents with cyanosis of unknown etiology. Postnatal echocardiography is the gold standard to confirm the anatomy and diagnosis of TOF along with other possible associated anomalies. The exact embryologic pathogenesis of how TOF occurs is unknown, however, it is hypothesized that defective partitioning of the conotruncus during septation accompanied by incomplete rotation results in two unequally sized vessels resulting in a conal septum that deviates far anteriorly according to Wise-Faberowski, et al.3. Several variants of TOF exist along with additional anomalies, including anomalous pulmonary venous drainage, atrial septal defect, and an interrupted inferior vena cava, to name a few.3 Additionally, there are genetic conditions associated with TOF including DiGeorge, CHARGE, VACTERL, and Trisomy 21.3 Efforts have been made to identify cellular mutations contributing to TOF, including Jagged1 (Jag1) mutations4 and mutations in the ZFPM2/FOG2 gene.5 Despite these findings, there continues to be a gap in knowledge regarding factors contributing to the cellular pathogenesis of TOF.

Since the contributing factors to TOF development are unclear, there is a need to investigate abnormalities occurring at the cellular level. HAND1 (eHAND, HXT, Thing 1) and HAND2 (dHAND, HED, Thing 2) are bHLH transcription factors that are involved in determining the formation of both the right and left ventricles.6 In this journal issue, Qi, et al.7, build on their prior discoveries of variants in the gene promoter regions such as ISL1, MYH6, and CITED2 in TOF patients, and hypothesize that variants in the HAND1 gene promoter could play a role in the formation of TOF. Their study evaluates variants of the HAND1 gene promoter region in the pathogenesis of TOF, which has not been explored in this population. Herein, we comment on the strengths and limitations of the Qi et al. translational study.7

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  1. Division of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Jamie Gilley & Binoy Shivanna

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  1. Jamie Gilley
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  2. Binoy Shivanna
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Correspondence to Binoy Shivanna.

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Gilley, J., Shivanna, B. Genetic advances in sporadic tetralogy of Fallot: discovery of novel HAND1 promoter variants. Pediatr Res 97, 1770–1771 (2025). https://doi.org/10.1038/s41390-024-03796-y

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