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


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.

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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”.

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Authors and Affiliations



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.

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Correspondence to Jean-François Avierinos or Stéphane Zaffran.

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The authors declare no competing interests.

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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.

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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).

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