Abstract
The etiology of congenital heart disease (CHD) is complex, comprising both genetic and environmental factors. Despite documented familial occurrences, the genetic etiology remains largely elusive. Trio exome sequencing identified a heterozygous FLT4 splice site variant in two families with respectively tetralogy of Fallot (TOF), and variable CHD comprising both the TOF spectrum and aortic coarctation. In the first family, Sanger sequencing on cDNA confirmed aberrant splicing for the c.985+1G > A variant. In the second family, transcriptome sequencing uncovered altered splicing for the c.1657+6T > C variant, despite normal targeted Sanger sequencing. In conclusion, our study establishes FLT4 splice site variants as a molecular cause of both left and right-sided isolated CHD, with incomplete penetrance. RNA-sequencing emerges as a valuable technique in unraveling the missing inheritability of CHD.
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Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. All variants have been submitted to the Clinvar database and can be accessed using the following accession numbers: SCV005407801 for NM_182925.5: c.1657+6T > C, and SCV005407803 for NM_182925.5: c.985+1G > A.
Change history
12 March 2025
The original online version of this article was revised: Author Tim Van Damme’s name was incorrectly written as Tim Vandamme.
01 April 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41431-025-01831-y
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Acknowledgements
The authors thank the families for their kind availability in sharing the findings within the scientific community.
Funding
This project was supported by a grant “Scientific research on heart diseases (2023)” from the Philanthropic Center Pelicano to BC and by a Research Grant of the Research Foundation—Flanders (G035620N) to BC. BC is a senior clinical investigator of the Research Foundation—Flanders.
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Conceptualization, MV, TV, SV, and BC; methodology, ED, LD, BM, SS, PC, and SV; validation, ED, LD, SS, PC, and BC; formal analysis, MV, ED, and LD; investigation, MV, ED, and TV; resources, LM, KD, KV, JP, ER, TV, and BC; data curation, ED, LD, BM, and SV; writing—original draft preparation, MV, and BC; writing—review and editing, all authors; visualization, MV, ED, and LD; supervision, BC; project administration, BC; funding acquisition, BC. All authors have read and agreed to the published version of the manuscript.
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This study was conducted in accordance with the 1984 Declaration of Helsinki and its subsequent revisions. The legal guardians of the individuals involved in this study provided written informed consent for the disclosure of case details.
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The original online version of this article was revised: Author Tim Van Damme’s name was incorrectly written as Tim Vandamme.
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Verlee, M., D’haenens, E., De Cock, L. et al. RNA-sequencing unveils FLT4 splice site variants in variable congenital heart disease. Eur J Hum Genet 33, 1085–1089 (2025). https://doi.org/10.1038/s41431-025-01788-y
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DOI: https://doi.org/10.1038/s41431-025-01788-y
