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A Novel Somatic Variant in HEY2 Unveils an Alternative Splicing Isoform Linked to Ventricular Septal Defect

  • Manal Fardon
  • Hassan Dehaini
  • Amina Kamar
  • Fadi Bitar
  • Marianne Majdalani
  • Issam El-Rassi
  • Georges Nemer
  • Mariam ArabiEmail author
Original Article

Abstract

Congenital heart defects (CHDs) are the leading cause of death in infants under 1 year of age. Aberrations in the expression and function of cardiac transcription factors (TFs) are a major contributor to CHDs. Despite the numerous studies undertaken to functionally characterize these TFs, their exact role in different stages of cardiogenesis is still not fully elucidated. Here we focused on HEY2, a basic helix loop helix transcriptional repressor, and its potential role in human ventricular septal defects. Genetic analysis was performed based on sequencing of DNA and cDNA obtained from post-operational cardiac tissues and blood of 17 Lebanese patients with various CHDs. The screen covered the entire coding regions of the GATA4, NKX2.5, TBX5, TBX20 and HEY2 genes. Our results revealed two novel somatic mutations, namely p.Ala229Thr and p.161_190 del, affecting HEY2 in the diseased cardiac tissues of two patients with VSD. These results suggest a potential role of HEY2 in regulating ventricular septation in humans.

Keywords

Congenital heart defects Ventricular septal defect Cardiac transcription factors HEY2 Mutation 

Notes

Acknowledgements

We thank all patients for their participation in the study. Special thanks to Mrs. Inaam El-Rassy in the Molecular Core facility for Sanger sequencing. This work was supported by an MPP/URB Grant from the American University of Beirut.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Supplementary material

246_2019_2099_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 kb)

References

  1. 1.
    Tennant PW, Pearce MS, Bythell M, Rankin J (2010) 20-year survival of children born with congenital anomalies: a population-based study. Lancet (London, England) 375(9715):649–656.  https://doi.org/10.1016/s0140-6736(09)61922-x CrossRefGoogle Scholar
  2. 2.
    Wren C, Irving CA, Griffiths JA, O’Sullivan JJ, Chaudhari MP, Haynes SR, Smith JH, Hamilton JR, Hasan A (2012) Mortality in infants with cardiovascular malformations. Eur J Pediatr 171(2):281–287.  https://doi.org/10.1007/s00431-011-1525-3 CrossRefGoogle Scholar
  3. 3.
    Khoshnood B, Lelong N, Houyel L, Thieulin AC, Jouannic JM, Magnier S, Delezoide AL, Magny JF, Rambaud C, Bonnet D, Goffinet F (2012) Prevalence, timing of diagnosis and mortality of newborns with congenital heart defects: a population-based study. Heart (British Cardiac Society) 98(22):1667–1673.  https://doi.org/10.1136/heartjnl-2012-302543 Google Scholar
  4. 4.
    Liu S, Joseph KS, Lisonkova S, Rouleau J, Van den Hof M, Sauve R, Kramer MS (2013) Association between maternal chronic conditions and congenital heart defects: a population-based cohort study. Circulation 128(6):583–589.  https://doi.org/10.1161/circulationaha.112.001054 CrossRefGoogle Scholar
  5. 5.
    Oster ME, Lee KA, Honein MA, Riehle-Colarusso T, Shin M, Correa A (2013) Temporal trends in survival among infants with critical congenital heart defects. Pediatrics 131(5):e1502–e1508.  https://doi.org/10.1542/peds.2012-3435 CrossRefGoogle Scholar
  6. 6.
    van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58(21):2241–2247.  https://doi.org/10.1016/j.jacc.2011.08.025 CrossRefGoogle Scholar
  7. 7.
    Hoffman JI (1990) Congenital heart disease: incidence and inheritance. Pediatr Clin N Am 37(1):25–43CrossRefGoogle Scholar
  8. 8.
    Benson DW (2002) The genetics of congenital heart disease: a point in the revolution. Cardiol Clin 20(3):385–394CrossRefGoogle Scholar
  9. 9.
    Clark KL, Yutzey KE, Benson DW (2006) Transcription factors and congenital heart defects. Annu Rev Physiol 68:97–121.  https://doi.org/10.1146/annurev.physiol.68.040104.113828 CrossRefGoogle Scholar
  10. 10.
    McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277.  https://doi.org/10.1016/B978-0-12-387786-4.00008-7 CrossRefGoogle Scholar
  11. 11.
    Donovan J, Kordylewska A, Jan YN, Utset MF (2002) Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice. Curr Biol 12(18):1605–1610CrossRefGoogle Scholar
  12. 12.
    Fischer A, Klamt B, Schumacher N, Glaeser C, Hansmann I, Fenge H, Gessler M (2004) Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mamm Genome 15(9):711–716.  https://doi.org/10.1007/s00335-004-2389-x CrossRefGoogle Scholar
  13. 13.
    Anderson DJ, Kaplan DI, Bell KM, Koutsis K, Haynes JM, Mills RJ, Phelan DG, Qian EL, Leitoguinho AR, Arasaratnam D, Labonne T, Ng ES, Davis RP, Casini S, Passier R, Hudson JE, Porrello ER, Costa MW, Rafii A, Curl CL, Delbridge LM, Harvey RP, Oshlack A, Cheung MM, Mummery CL, Petrou S, Elefanty AG, Stanley EG, Elliott DA (2018) NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nat Commun 9(1):1373.  https://doi.org/10.1038/s41467-018-03714-x CrossRefGoogle Scholar
  14. 14.
    Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112(4):707–720.  https://doi.org/10.1161/circresaha.112.300853 CrossRefGoogle Scholar
  15. 15.
    Fischer A, Gessler M (2003) Hey genes in cardiovascular development. Trends Cardiovasc Med 13(6):221–226CrossRefGoogle Scholar
  16. 16.
    (2018) https://www.ncbi.nlm.nih.gov/gene/23493. Accessed 2 Feb 2018
  17. 17.
    Koibuchi N, Chin MT (2007) CHF1/Hey2 plays a pivotal role in left ventricular maturation through suppression of ectopic atrial gene expression. Circ Res 100(6):850–855.  https://doi.org/10.1161/01.RES.0000261693.13269.bf CrossRefGoogle Scholar
  18. 18.
    Miao L, Li J, Li J, Tian X, Lu Y, Hu S, Shieh D, Kanai R, Zhou BY, Zhou B, Liu J, Firulli AB, Martin JF, Singer H, Zhou B, Xin H, Wu M (2018) Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification. Sci Rep 8(1):2678.  https://doi.org/10.1038/s41598-018-20917-w CrossRefGoogle Scholar
  19. 19.
    Yehya A, Souki R, Bitar F, Nemer G (2006) Differential duplication of an intronic region in the NFATC1 gene in patients with congenital heart disease. Genome 49(9):1092–1098.  https://doi.org/10.1139/g06-072 CrossRefGoogle Scholar
  20. 20.
    Yang YQ, Wang J, Liu XY, Chen XZ, Zhang W, Wang XZ, Liu X, Fang WY (2012) Novel GATA4 mutations in patients with congenital ventricular septal defects. Med Sci Monit 18(6):Cr344–Cr350CrossRefGoogle Scholar
  21. 21.
    Simpson L, Emeson RB (1996) RNA editing. Annu Rev Neurosci 19:27–52.  https://doi.org/10.1146/annurev.ne.19.030196.000331 CrossRefGoogle Scholar
  22. 22.
    van Leeuwen FW, Burbach JP, Hol EM (1998) Mutations in RNA: a first example of molecular misreading in Alzheimer’s disease. Trends Neurosci 21(8):331–335CrossRefGoogle Scholar
  23. 23.
    Laxminarayana D, Kammer GM (2000) mRNA mutations of type I protein kinase A regulatory subunit alpha in T lymphocytes of a subject with systemic lupus erythematosus. Int Immunol 12(11):1521–1529CrossRefGoogle Scholar
  24. 24.
    Reamon-Buettner SM, Borlak J (2005) HEY2 Mutations in Malformed Hearts. Hum Mutat 27(1):118CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Manal Fardon
    • 1
  • Hassan Dehaini
    • 2
  • Amina Kamar
    • 2
  • Fadi Bitar
    • 3
  • Marianne Majdalani
    • 3
  • Issam El-Rassi
    • 4
  • Georges Nemer
    • 1
  • Mariam Arabi
    • 3
    Email author
  1. 1.Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon
  2. 2.Department of BiologyAmerican University of BeirutBeirutLebanon
  3. 3.Department of Pediatrics and Adolescent MedicineAmerican University of BeirutBeirutLebanon
  4. 4.Department of SurgeryAmerican University of BeirutBeirutLebanon

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