Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Identification of non-synonymous variations in ROBO1 and GATA5 genes in a family with bicuspid aortic valve disease

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect with a high index of heritability. Patients with BAV have different clinical courses and disease progression. Herein, we report three siblings with BAV and clinical differences. Their clinical presentations include moderate to severe aortic regurgitation, aortic stenosis, and ascending aortic aneurysm. Genetic investigation was carried out using Whole-Exome Sequencing for the three patients. We identified two non-synonymous variants in ROBO1 and GATA5 genes. The ROBO1: p.(Ser327Pro) variant is shared by the three BAV-affected siblings. The GATA5: p.(Gln3Arg) variant is shared only by the two brothers who presented BAV and ascending aortic aneurysm. Their sister, affected by BAV without aneurysm, does not harbor the GATA5: p.(Gln3Arg) variant. Both variants were absent in the patients’ fourth brother who is clinically healthy with tricuspid aortic valve. To our knowledge, this is the first association of ROBO1 and GATA5 variants in familial BAV with a potential genotype-phenotype correlation. Our findings are suggestive of the implication of ROBO1 gene in BAV and the GATA5: p.(Gln3Arg) variant in ascending aortic aneurysm. Our family-based study further confirms the intrafamilial incomplete penetrance of BAV and the complex pattern of inheritance of the disease.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. Michelena HI, Prakash SK, Della Corte A, Bissell MM, Anavekar N, Mathieu P, et al. Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon). Circulation. 2014;129:2691–704.

    Article  Google Scholar 

  2. Martín M, Lorca R, Rozado J, Alvarez-Cabo R, Calvo J, Pascual I, et al. Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity. J Thorac Dis. 2017;9:S454–64.

    Article  Google Scholar 

  3. Tessler I, Albuisson J, Goudot G, Carmi S, Shpitzen S, Messas E, et al. Bicuspid aortic valve: genetic and clinical insights. AORTA J. 2021;9:139–46.

    Article  Google Scholar 

  4. Martin LJ, Pilipenko V, Kaufman KM, Cripe L, Kottyan LC, Keddache M, et al. Whole exome sequencing for familial bicuspid aortic valve identifies putative variants. Circ Cardiovasc Genet. 2014;7:677–83.

    Article  CAS  Google Scholar 

  5. Tessler I, Goudot G, Albuisson J, Reshef N, Zwas DR, Carmi S, et al. Is bicuspid aortic valve morphology genetically determined? A family-based study. Am J Cardiol. 2022;163:85–90.

    Article  CAS  Google Scholar 

  6. Galian-Gay L, Carro Hevia A, Teixido-Turà G, Rodríguez Palomares J, Gutiérrez-Moreno L, Maldonado G, et al. Familial clustering of bicuspid aortic valve and its relationship with aortic dilation in first-degree relatives. Heart. 2018;heartjnl-2018-313802.

  7. Hui DS, Bonow RO, Stolker JM, Braddock SR, Lee R. Discordant aortic valve morphology in monozygotic twins: a clinical case series. JAMA Cardiol. 2016;1:1043–7.

    Article  Google Scholar 

  8. Saravanan P, Kadir I. Apolipoprotein E alleles and bicuspid aortic valve stenosis in monozygotic twins. Interact Cardiovasc Thorac Surg. 2009;8:687–8.

    Article  Google Scholar 

  9. Foffa I, Ait Alì L, Panesi P, Mariani M, Festa P, Botto N, et al. Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve. BMC Med Genet. 2013;14:44.

    Article  CAS  Google Scholar 

  10. Musfee FI, Guo D, Pinard AC, Hostetler EM, Blue EE, Nickerson DA, et al. Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease. Mol Genet Genom Med. 2020;8:e1406.

    CAS  Google Scholar 

  11. Bonachea EM, Chang S-W, Zender G, LaHaye S, Fitzgerald-Butt S, McBride KL, et al. GATA5 sequence variants identified in individuals with bicuspid aortic valve. Pediatr Res. 2014;76:211–6.

    Article  CAS  Google Scholar 

  12. Laforest B, Nemer M. GATA5 interacts with GATA4 and GATA6 in outflow tract development. Dev Biol. 2011;358:368–78.

    Article  CAS  Google Scholar 

  13. Zhao J, Mommersteeg MTM Slit–Robo signalling in heart development. Cardiovasc Res. 2018;114:794–804.

  14. Medioni C, Bertrand N, Mesbah K, Hudry B, Dupays L, Wolstein O, et al. Expression of slit and robo genes in the developing mouse heart. Dev Dyn Publ Am Assoc Anat. 2010;239:3303–11.

    CAS  Google Scholar 

  15. Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, et al. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet. 2019;51:42–50.

    Article  CAS  Google Scholar 

  16. Kruszka P, Tanpaiboon P, Neas K, Crosby K, Berger SI, Martinez AF, et al. Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. J Med Genet. 2017;54:825–9.

    Article  Google Scholar 

  17. Desvignes J-P, Bartoli M, Delague V, Krahn M, Miltgen M, Béroud C, et al. VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res. 2018;46:W545–53.

    Article  CAS  Google Scholar 

  18. Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67.

    Article  Google Scholar 

  19. Ackerman C, Locke AE, Feingold E, Reshey B, Espana K, Thusberg J, et al. An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects. Am J Hum Genet. 2012;91:646–59.

    Article  CAS  Google Scholar 

  20. Padang R, Bagnall RD, Richmond DR, Bannon PG, Semsarian C. Rare non-synonymous variations in the transcriptional activation domains of GATA5 in bicuspid aortic valve disease. J Mol Cell Cardiol. 2012;53:277–81.

    Article  CAS  Google Scholar 

  21. Tong M, Jun T, Nie Y, Hao J, Fan D. The role of the slit/robo signaling pathway. J Cancer. 2019;10:2694–705.

    Article  CAS  Google Scholar 

  22. Le Bras A. ROBO4 variants linked to congenital heart defects. Nat Rev Cardiol. 2019;16:70.

    Article  Google Scholar 

  23. Mommersteeg MTM, Yeh ML, Parnavelas JG, Andrews WD. Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves. Cardiovasc Res. 2015;106:55–66.

    Article  CAS  Google Scholar 

  24. Phillips HM, Mahendran P, Singh E, Anderson RH, Chaudhry B, Henderson DJ. Neural crest cells are required for correct positioning of the developing outflow cushions and pattern the arterial valve leaflets. Cardiovasc Res. 2013;99:452–60.

    Article  CAS  Google Scholar 

  25. Odelin G, Faure E, Coulpier F, Di Bonito M, Bajolle F, Studer M, et al. Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. Dev Camb Engl. 2018;145:dev151944.

    Google Scholar 

  26. Wei D, Bao H, Zhou N, Zheng G-F, Liu X-Y, Yang Y-Q. GATA5 loss-of-function mutation responsible for the congenital ventriculoseptal defect. Pediatr Cardiol. 2013;34:504–11.

    Article  Google Scholar 

  27. Jiang J-Q, Li R-G, Wang J, Liu X-Y, Xu Y-J, Fang W-Y, et al. Prevalence and spectrum of GATA5 mutations associated with congenital heart disease. Int J Cardiol. 2013;165:570–3.

    Article  Google Scholar 

  28. Morrisey EE, Ip HS, Tang Z, Parmacek MS. GATA-4 activates transcription via two novel domains that are conserved within the GATA-4/5/6 subfamily. J Biol Chem. 1997;272:8515–24.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the family for their collaboration. This work was supported by the “Association Française contre les Myopathies-AFM Telethon” [MoThARD-Project], and the “Institut National de la Santé et de la Recherche Médicale” to SZ. HJ received Postdoctoral fellowships from the “Association Française contre les Myopathies-AFM Telethon”.

Author information

Authors and Affiliations

Authors

Contributions

Study concept and design: JFA, SZ; Clinical Investigation of the patients and family members; HG, AT, FC, JFA; Analysis and interpretation of data: GCB, HJ. Molecular investigation: HJ.; Writing—Original draft preparation: HJ; HG; Critical—review & editing: AT, JFA, SZ. Supervision: SZ; Validation: SZ, JFA.

Corresponding authors

Correspondence to Jean-François Avierinos or Stéphane Zaffran.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

This study was performed according to the principles of the Declaration of Helsinki and to the ethical standards of the first author’s institutional review board. The patients provided their written informed consent to participate in this study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jaouadi, H., Gérard, H., Théron, A. et al. Identification of non-synonymous variations in ROBO1 and GATA5 genes in a family with bicuspid aortic valve disease. J Hum Genet 67, 515–518 (2022). https://doi.org/10.1038/s10038-022-01036-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-022-01036-x

Search

Quick links