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A novel heterozygous pathogenic variant in HEY2 led to a familial form of non-syndromic Tetralogy of Fallot

European Journal of Human Genetics volume 33, pages 1072–1075 (2025)Cite this article

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Abstract

Tetralogy of Fallot (TOF) aetiologies remain largely unknown. Although syndromes with genetic cause have been involved, non-syndromic TOF are not completely elucidated, with a genetic diagnosis in less than 20% of the cases. HEY2 is a basic helix-loop-helix (bHLH) repressive transcription factor implicated in cardiac development. In this study, we identify a novel heterozygous missense variant in HEY2 gene segregating within a family presenting with non-syndromic TOF with autosomal dominant transmission. The identified variation c.171 G > C p.(Glu57Asp) was tested through gene reporter assay, revealing a complete disruption of HEY2 repressive activity. These results suggest that HEY2 is a novel gene implicated in the pathogenesis of Tetralogy of Fallot, expanding the genetic spectrum of this congenital heart defect and reinforcing the role of monogenic contributions in non-syndromic TOF.

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Fig. 1: Tetralogy of Fallot family presentation.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. The variant has been submitted to Clinvar database under the accession number VCV003777042.1.

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Funding

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Service de génétique médicale, CHU de Bordeaux, Bordeaux, F-33000, France

    Camille Bergès & Caroline Rooryck

  2. Service de Génétique Médicale, CHU de Clermont Ferrand, Clermont Ferrand, France

    Fanny Laffargue

  3. Service de Cardiologie, CHU de Clermont Ferrand, Clermont Ferrand, France

    Claire Dauphin

  4. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Alex-Vincent Postma

  5. Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Alex-Vincent Postma

  6. Service des cardiopathies congénitales, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France

    Jean-Benoit Thambo

  7. IHU LYRIC, Pessac, France

    Jean-Benoit Thambo & Caroline Rooryck

  8. Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U1211 INSERM, Bordeaux, France

    Caroline Rooryck

Authors
  1. Camille Bergès
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  2. Fanny Laffargue
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  3. Claire Dauphin
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  4. Alex-Vincent Postma
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  5. Jean-Benoit Thambo
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  6. Caroline Rooryck
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Contributions

C.B and C.R wrote the main manuscript and prepared figures. AV.P performed the in vitro experiments. All authors have contributed to the manuscript elaboration and have reviewed it.

Corresponding authors

Correspondence to Camille Bergès or Caroline Rooryck.

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Competing interests

The authors declare no competing interests.

Ethical approval

As this study is based on a familial case report with informed patient consent, formal ethical approval was not required under institutional guidelines.

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Bergès, C., Laffargue, F., Dauphin, C. et al. A novel heterozygous pathogenic variant in HEY2 led to a familial form of non-syndromic Tetralogy of Fallot. Eur J Hum Genet 33, 1072–1075 (2025). https://doi.org/10.1038/s41431-025-01880-3

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