Elucidation of the genetic causes of bicuspid aortic valve disease

Gehlen, Jan; Stundl, Anja; Debiec, Radoslaw; Fontana, Federica; Krane, Markus; Sharipova, Dinara; Nelson, Christopher P.; Al‐Kassou, Baravan; Giel, Ann Sophie; Sinning, Jan Malte; Bruenger, Christopher Mh; Zelck, Carolin; Koebbe, Laura L; Braund, Peter S.; Webb, Tom R.; Hetherington, Simon; Ensminger, Stephan; Fujita, Buntaro; Mohamed, Salah A.; Shrestha, Malakh; Krueger, Heike; Siepe, Matthias; Kari, Fabian A.; Nordbeck, Peter; Buravezky, Larissa; Kelm, Malte; Veulemans, Verena; Adam, Matti; Baldus, Stephan; Laugwitz, Karl‐Ludwig; Haas, Yannick; Kretzler, Matthias; Mehlhorn, Uwe; Conzelmann, Lars O.; Breitenbach, Ingo; Lebherz, Corinna; Urbanski, Paul P.; Kim, Won Keun; Kandels, J; Ellinghaus, David; Nowak-Goettl, Ulrike; Hoffmann, Per; Wirth, Fabian; Doppler, S.; Lahm, Harald; Dreßen, Martina; Scheidt, Moritz von; Knoll, Katharina; Kessler, Thorsten; Hengstenberg, Christian; Schunkert, Heribert; Nickenig, Georg; Nöthen, Markus M.; Bolger, Aidan P.; Abdelilah‐Seyfried, Salim; Samani, Nilesh J.; Erdmann, Jeanette; Trenkwalder, Teresa; Schumacher, Johannes

doi:10.1093/cvr/cvac099

Cited by 18 publications

(22 citation statements)

References 62 publications

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“…In this study, we identified heterozygous HOXA1 dominant negative mutations in humans with BAV. Several studies showed that BAV is a polygenic disorder 4,24 , so we cannot exclude that HOXA1 variants act in concert with other genetic factors to contribute to the onset of the BAV phenotype. Using in vivo experiments, we demonstrated that homozygous Hoxa1knock-out and Hoxa1 −1His knock-in mice present BAV, and that targeting the zebrafish hoxa1a ortholog resulted in aortic valve defects that could be rescued by expressing the wild-type human HOXA1.…”

Section: Discussionmentioning

confidence: 94%

“…To further examine if variants in genes associated with BAV (e.g. NOTCH1, GATA4, GATA5, MUC4, and ROBO4) and implicated in valvular and aortic defects were present in individuals carrying deletion or insertion in the poly-histidine tract of HOXA1, we performed exome sequencing 16,17,19,24 . After exome sequencing analysis no relevant variants were identified except for three missense variants in NOTCH1 and GATA5 genes.…”

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

confidence: 99%

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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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Section: Discussionmentioning

confidence: 94%

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

confidence: 99%

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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“…Interestingly, the duplication CNV associated with BAV in TS is also associated with conotruncal defects and left-sided lesions in 22q11.2 deletion syndrome suggesting that genetic modifiers of CHD may manifest differently on different high-risk backgrounds (Prakash et al 2016 ). CRELD1 has not been implicated in the pathogenesis of non-syndromic, non-familial BAV via GWAS (Helgadottir et al 2018 ; Fulmer et al 2019 ; Bjornsson et al 2018 ; Yang et al 2017 ; Gehlen et al 2022 ; Gago-Díaz et al 2017 ). Thus, the effect of CRELD1 variants may be more penetrant in the setting of Xchr haploinsufficiency, representing an as-of-yet unidentified mechanism contributing to the polygenic heritability of BAV.…”

Section: Discussionmentioning

confidence: 99%

CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome

et al. 2023

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Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of the second sex chromosome and exhibits phenotypic heterogeneity, even after accounting for mosaicism and karyotypic variation. Congenital heart defects (CHD) are found in up to 45 percent of girls with TS and span a phenotypic continuum of obstructive left-sided lesions, with bicuspid aortic valve (BAV) being the most common. Several recent studies have demonstrated a genome-wide impact of X chromosome haploinsufficiency, including global hypomethylation and altered RNA expression. The presence of such broad changes to the TS epigenome and transcriptome led others to hypothesize that X chromosome haploinsufficiency sensitizes the TS genome, and several studies have demonstrated that a second genetic hit can modify disease susceptibility in TS. The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants in CRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare variants in CRELD1 have been associated with both syndromic and non-syndromic CHD. This observation supports the hypothesis that genetic modifiers outside the X chromosome that lie in known heart development pathways may influence CHD risk in TS.

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“…The genetic basis of CAVD is complex, as exemplified by the gene-phenotype linkage of BAV, a congenital valve abnormality with strikingly variable genetic etiologies, ranging from intricate inheritance patterns to sporadic cases. Beyond certain syndromes and congenital malformations involving the left ventricular outflow tract, the heritability of BAV appears to be largely polygenic, 13 with an up to 10-fold increased prevalence in first-degree relatives as compared to the general population. In a recent GWAS involving 466 BAV cases and 4660 controls, a noncoding variant near GATA4 (rs6601627) reached genome-wide significance with a protein-altering variant in this cardiac-specific transcription factor (rs3729856) showing near-significant association.…”

Section: (Epi-)genome: a Crucial Determinant Of Aortic Valve Calcific...mentioning

confidence: 99%

Network-Guided Multiomic Mapping of Aortic Valve Calcification

Blaser

Kraler

Lüscher

et al. 2023

ATVB

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Despite devastating clinical sequelae of calcific aortic valve disease that range from left ventricular remodeling to arrhythmias, heart failure, and early death, the molecular insights into disease initiation and progression are limited and pharmacotherapies remain unavailable. The pathobiology of calcific aortic valve disease is complex and comprehensive studies are challenging valvular calcification is heterogeneous and occurs preferentially on the aortic surface, along a fibrocalcific spectrum. Here, we review efforts to study (epi-)genomic, transcriptomic, proteomic, and metabolomic aspects of aortic valve calcification in combination with network medicine-/systems biology-based strategies to integrate multilayered omics datasets and prioritize druggable targets for experimental validation studies. Ultimately, such holistic approach efforts may open therapeutic avenues that go beyond invasive and costly valve replacement therapy.

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Elucidation of the genetic causes of bicuspid aortic valve disease

Cited by 18 publications

References 62 publications

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

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

CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome

Network-Guided Multiomic Mapping of Aortic Valve Calcification

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