Clinical insights into a tertiary care center cohort of patients with bicuspid aortic valve

Théron, Alexis; Touil, A.; Resseguier, Noémie; Collod‐Béroud, Gwenaëlle; Norscini, Giulia; Simoni, A; Odelin, Gaëlle; Habib, Gilbert; Collart, Frédéric; Zaffran, Stéphane; Avierinos, Jean-François

doi:10.1007/s10554-021-02366-1

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…The clinical characteristics of the study participants are summarized in Table 1. As previously reported 20 , there are more men (225) presented in this cohort compared with women (80; sex ratio = 73.8%). Also, the average age, 54.1 ± 15.6 years, is slightly higher than previously reported for BAV cohorts 21 .…”

Section: Resultssupporting

confidence: 83%

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Odelin

Faucherre

Marchese

et al. 2022

Preprint

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Bicuspid aortic valve (BAV) is the most common cardiovascular malformation (0.5–1.2% of the population) and is often associated with premature aortic valve stenosis or insufficiency, aortic aneurysm and other congenital cardiac heart defects. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the association of novel variants in the transcription factor HOXA1 with BAV in humans. Targeted sequencing of HOXA1 in a cohort of 333 BAV patients identified rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis revealed that disruption of the histidine repeat motif causes a significant reduction in the half-life of the protein, and that these variants are associated with a defective transcriptional activity of the HOXA1 protein. Targeting the zebrafish hoxa1a ortholog in vivo resulted in aortic valve defects that could be rescued by expressing the wild-type human HOXA1. Furthermore, expression of HOXA1 Histidine variants in zebrafish also impacted aortic valve development indicating a dominant negative effect of these mutated proteins. Lastly, homozygous knockout mice for Hoxa1 develop a BAV phenotype, which is associated with a very small, rudimentary non-coronary leaflet. Genetic lineage analysis indicates that this defect is caused by a strong reduction of mesenchymal cells in the intercalated cushion due to a failure of neural crest cell migration toward the heart which is consistent with our transcriptomic analysis showing a down-regulation of premigratory and migratory neural crest markers in Hoxa1−/− compared with control embryos. Together, these findings indicate that variants causing HOXA1 dysfunction play a significant role in the genetic cause of BAV in humans.

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Section: Resultssupporting

confidence: 83%

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Odelin

Faucherre

Marchese

et al. 2022

Preprint

Self Cite

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“…The clinical characteristics of the study participants are summarized in Table 1. As previously reported 22 , there are more men (249) presented in this cohort compared with women (84; sex ratio = 74.77%). Also, the average age, 52.39 ± 14.94 years, is slightly higher than previously reported for BAV cohorts 23 .…”

Section: Identification Of Indel Variants In the Poly-histidine Tract...supporting

confidence: 82%

Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Odelin

Faucherre²,

Marchese³

et al. 2023

Nat Commun

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Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1−1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1−/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.

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“…From a cohort of 40 BAV adult patients [ 26 ] and 20 BAV pediatric cases, we sought to determine the implication of the ROBO-SLIT pathway in patients with no relevant variants in known BAV-related genes. Interestingly, the yield of rare variants in ROBO and SLIT genes was greater in the pediatric cohort (13/20, 65%) compared to only 4 out 40 BAV cases (10%) from the adult cohort (Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

et al. 2023

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Background Recent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD). Methods We have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability. Results A total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4: p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4: c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development. Conclusion Our results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests.

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Clinical insights into a tertiary care center cohort of patients with bicuspid aortic valve

Cited by 4 publications

References 25 publications

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

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