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Minor alleles of genetic variants in second heart field increase the risk of hypoplastic right heart syndrome

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Abstract

Hypoplastic right heart syndrome (HRHS) is characterized by hypoplastic right ventricle (RV); Numerous transcriptional cascades in the second heart field (SHF) regulate RV development. The relationship of SHF gene variants with human HRHS remains unknown. The whole lengths of 17 SHF genes were sequenced in 16 HRHS, and the selected single-nucleotide variants (SNVs) were then genotyped in HRHS, other congenital heart disease (CHD) and healthy control. Luciferase assay was performed to verify the effect of FOXC2: rs34221221 \(\hbox {A}{>}\hbox {G}\) and TBX20: rs59854940 \(\hbox {C}{>}\hbox {G}\) at the transcription level. There were 151 (12.86%) novel SNVs after sequence analysis, of which three were in exons (one was synonymous SNV and two were nonsynonymous SNVs), two in promoter, and most SNVs (89.95%) were in intronic regions. Genotype analyses revealed that the minor alleles of FOXC2: rs34221221 \(\hbox {A}{>}\hbox {G}\) and TBX20: rs59854940 \(\hbox {C}{>}\hbox {G}\) could increase HRHS risk (\(P{<}0.05\)), but not in other CHD or healthy control. Luciferase assay showed that the minor G allele in rs34221221 significantly increased FOXC2 transcription while in rs59854940 it decreased TBX20 transcription significantly. Novel variants of SHF gene associated with HRHS were identified. Minor alleles in two variants from FOXC2 and TBX20 could increase the risk of HRHS.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant no. 81400242, 81430006 and 81441010) and the National Basic Research Development Program in China (Program 973: 2010CB529505).

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Author notes

  1. Enshi Wang, Yu Nie and Xuesong Fan contributed equally on this work.

Authors and Affiliations

  1. Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing,  100037, People’s Republic of China

    Enshi Wang, Zhe Zheng, Haiyong Gu, Hao Zhang & Shengshou Hu

  2. State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing,  100037, People’s Republic of China

    Enshi Wang, Yu Nie, Hao Zhang & Shengshou Hu

  3. Department of Clinical Laboratory Center, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing,  100029, People’s Republic of China

    Xuesong Fan

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  1. Enshi Wang
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Correspondence to Shengshou Hu.

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Corresponding Editor: H. A. Ranganath

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Wang, E., Nie, Y., Fan, X. et al. Minor alleles of genetic variants in second heart field increase the risk of hypoplastic right heart syndrome. J Genet 98, 45 (2019). https://doi.org/10.1007/s12041-019-1092-3

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  • DOI: https://doi.org/10.1007/s12041-019-1092-3

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