A de novo pathogenic BMP2 variant-related phenotype with the novel finding of bicuspid aortic valve.
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ABSTRACT:
SUBMITTER: Ahluwalia N
PROVIDER: S-EPMC8548885 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
A de novo pathogenic BMP2 variant-related phenotype with the novel finding of bicuspid aortic valve.
Ahluwalia Neha N Gelb Bruce D BD
American journal of medical genetics. Part A 20201127 2
A rare autosomal dominant syndrome with craniofacial dysmorphisms, skeletal abnormalities, short stature, and congenital heart defects has recently been described, associated with monoallelic truncating and frameshift bone morphogenetic protein 2 (BMP2) variants and deletions. We describe a patient harboring a novel de novo BMP2 nonsense variant, who exhibited craniofacial and skeletal features previously described for this trait and the novel findings of bicuspid aortic valve (BAV) and aortic r ...[more]
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Project description:AimsTo compare the progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV).Methods and resultsOne hundred and forty-one patients with mild-to-moderate AS, recruited prospectively in the PROGRESSA study, were included in this sub-analysis. Baseline clinical, Doppler echocardiography and multidetector computed tomography characteristics were compared between BAV (n = 32) and TAV (n = 109) patients. The 2-year haemodynamic [i.e. peak aortic jet velocity (Vpeak) and mean transvalvular gradient (MG)] and anatomic [i.e. aortic valve calcification density (AVCd) and aortic valve calcification density ratio (AVCd ratio)] progression of AS were compared between the two valve phenotypes. The 2-year progression rate of Vpeak was: 16 (-0 to 40) vs. 17 (3-35) cm/s, P = 0.95; of MG was: 1.8 (-0.7 to 5.8) vs. 2.6 (0.4-4.8) mmHg, P = 0.56; of AVCd was 32 (2-109) vs. 52 (25-85) AU/cm2, P = 0.15; and of AVCd ratio was: 0.08 (0.01-0.23) vs. 0.12 (0.06-0.18), P = 0.16 in patients with BAV vs. TAV. In univariable analyses, BAV was not associated with AS progression (all, P ≥ 0.26). However, with further adjustment for age, AS baseline severity, and several risk factors (i.e. sex, history of hypertension, creatinine level, diabetes, metabolic syndrome), BAV was independently associated with faster haemodynamic (Vpeak: β = 0.31, P = 0.02) and anatomic (AVCd: β = 0.26, P = 0.03 and AVCd ratio: β = 0.26, P = 0.03) progression of AS.ConclusionIn patients with mild-to-moderate AS, patients with BAV have faster haemodynamic and anatomic progression of AS when compared to TAV patients with similar age and risk profile. This study highlights the importance and necessity to closely monitor patients with BAV and to adequately control and treat their risk factors.Clinical trial registrationhttps://clinicaltrials.gov Unique identifier: NCT01679431.
| S-EPMC7306858 | biostudies-literature
Project description:Introduction: Morphology of bicuspid aortic valve (BAV) may have implication in the associated pathologies including aortic stenosis (AS), aortic insufficiency (AI) and aortic dilation. The aim of this study is to investigate the frequency and patterns of valvular dysfunction and aortopathy associated with different phenotypes of BAV in a referral center in northwest of Iran. Methods: In this prospective study patients who presented to our echocardiography lab between January 2014 and December 2015 and were diagnosed with BAV were assessed. Frequency of various BAV phenotypes and their association with valvular dysfunction and aortopathy was evaluated. A P value less than 0.05 was considered statistically significant. Results: The average age of the study patients was 40±16 years, with predominance of male sex (72%). Patients with anteroposteriorly located BAV (BAV-AP) phenotype constituted majority of our cases with prevalence of 62.7%, while 37.3% of cases had right-left (BAV-RL) located valves. BAV-RL patients when compared to BAV-AP patients had higher frequencies of dilated aortic arch (25% vs. 4.3%, P < 0.001), AS (56.3% vs. 31.4%, P < 0.001), mass or vegetation on aortic valve (14.3 vs. 6.4%, P = 0.023) and lower frequencies of dilated aortic root (42.9% vs. 57.4%, P = 0.01), aortic insufficiency (68.8% vs. 79.8%, P = 0.034) and co-arctation of aorta (3.6% vs. 11.7%, P = 0.01). Conclusion: There seems to be a relationship between various BAV phenotypes, and frequency and pattern of aortic valve dysfunction and aortopathy. These findings suggest that examining leaflet morphology in BAV might help in risk stratification of these patients.
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| S-EPMC3697122 | biostudies-literature
Project description: Not available
| S-EPMC9871343 | biostudies-literature
Project description:Background. Bicuspid aortic valve (BAV) is a common congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant pattern of inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with other clinical manifestations in syndromic conditions. Identification of a syndromic condition in a BAV patient is clinically relevant in order to personalize indication to aortic surgery. We aimed to point out how genetic diagnosis by next-generation sequencing (NGS) can improve management of a patient with complex BAV clinical picture. Methods and Results. We describe a 45-year-old Caucasian male with BAV, thoracic aortic root and ascending aorta dilatation, and connective features evocative but inconclusive for clinical diagnosis of Marfan syndrome (MFS). Targeted (91 genes) NGS was used. Proband genetic variants were investigated in first-degree relatives. Proband carried 5 rare variants in 4 genes: FBN1(p.Asn542Ser and p.Lys2460Arg), NOTCH1(p.Val1739Met), LTBP1(p.Arg1330Gln), and TGFBR3(p.Arg423Trp). The two FBN1 variants were inherited in cis by the mother, showing systemic features evocative of MFS, but with a milder phenotype than that observed in the proband. Careful clinical observation along with the presence of the FBN1 variants allowed diagnosis of MFS in the proband and in his mother. NOTCH1 variant was found in mother and brother, not exhibiting BAV, thus not definitely supporting/excluding association with BAV. Interestingly, the proband, his brother and father, all showing root dilatation, and his sister, with upper range aortic root dimension, were carriers of a TGFBR3 variant. LTBP1 might also modulate the vascular phenotype. Conclusions. Our results underline the usefulness of NGS together with family evaluation in diagnosis of patients with monogenic traits and overlapping clinical manifestations due to contribution of the same genes and/or presence of comorbidities determined by different genes.
| S-EPMC6145047 | biostudies-literature
Project description:A 37-year-old male presented to the Emergency Department with acute worsening of back pain and new onset dyspnea. Transthoracic echocardiography revealed moderate left ventricular dysfunction and a bicuspid aortic valve (BAV). In addition, he was noted to have a dilated thoracic aorta concerning for a dissection, severe aortic insufficiency (AI), and both a pericardial and pleural effusion. Magnetic resonance imaging revealed a Type A ascending aortic dissection. He was taken emergently to the operating room for repair. An intraoperative transesophageal echocardiography examination was performed which revealed a normal trileaflet AV with a Type A aortic dissection flap masquerading as a BAV. The dissection flap interfered with both the valve's function, causing severe AI, as well as the valve's appearance, causing it to look bicuspid on echocardiography.
| S-EPMC5791272 | biostudies-literature
Project description:Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar loss-of-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.
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| S-EPMC6821178 | biostudies-literature
Project description:BackgroundValvular dysfunction is a common complication in patients with bicuspid aortic valves (BAV). The aim of this study was to determine the relationship between BAV morphology patterns and valve dysfunction.MethodsWe searched the PubMed, The Cochrane Library, Web of Science, and CNKI until May 31, 2020, to identify all studies investigating the morphology of BAV and valvular dysfunction, and data were extracted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Data were analyzed using Stata 15.1 software. The additional characteristics (gender, mean age) were collected to perform a meta-regression analysis.ResultsThirteen studies on BAV-RL (n = 2002) versus BAV-RN (n = 1254) and raphe (n = 4001) versus without raphe (n = 673) were included. The BAV-RL patients showed a higher incidence of aortic regurgitation than BAV-RN patients (OR = 1.46; 95% CI: 1.12 to 1.90, p = .005), while the BAV-RL patients showed a lower incidence of aortic stenosis than BAV-RN patients (OR = 0.66, 95% CI: 0.58 to 0.76, p = .000); BAV patients with raphe presents a higher incidence of aortic regurgitation than those without raphe (OR = 1.95, 95% CI: 1.12-3.39, p = .017). No differences were found between raphe and without raphe group in the incidence of aortic stenosis (OR = 0.97, 95% CI: 0.53 to 1.76, p = .907). Mean age and gender had no influence on observed differences.ConclusionsOur results confirmed a relationship between different BAV phenotypes and aortic valve dysfunction. BAV-RL and BAV with raphe are more likely to develop aortic regurgitation, while patients with BAV-RN present a higher possibility to develop aortic stenosis.
| S-EPMC8715397 | biostudies-literature
Project description:ObjectivesTo compare the outcomes after surgical (SAVR) and transcatheter aortic valve replacement (TAVR) for severe stenosis of bicuspid aortic valve (BAV).MethodsWe evaluated the early and mid-term outcome of patients with stenotic BAV who underwent SAVR or TAVR for aortic stenosis from the nationwide FinnValve registry.ResultsThe FinnValve registry included 6463 AS patients and 1023 (15.8%) of them had BAV. SAVR was performed in 920 patients and TAVR in 103 patients with BAV. In the overall series, device success after TAVR was comparable to SAVR (94.2% vs. 97.1%, p = 0.115). TAVR was associated with increased rate of mild-to-severe paravalvular regurgitation (PVR) (19.4% vs. 7.9%, p < 0.0001) and of moderate-to-severe PVR (2.9% vs. 0.7%, p = 0.053). When newer-generation TAVR devices were evaluated, mild-to-severe PVR (11.9% vs. 7.9%, p = 0.223) and moderate-to-severe PVR (0% vs. 0.7%, p = 1.000) were comparable to SAVR. Type 1 N-L and type 2 L-R/R-N were the BAV morphologies with higher incidence of mild-to-severe PVR (37.5% and 100%, adjusted for new-generation prostheses p = 0.025) compared to other types of BAVs. Among 75 propensity score-matched cohorts, 30-day mortality was 1.3% after TAVR and 5.3% after SAVR (p = 0.375), and 2-year mortality was 9.7% after TAVR and 18.7% after SAVR (p = 0.268) CONCLUSIONS: In patients with stenotic BAV, TAVR seems to achieve early and mid-term results comparable to SAVR. Type 1 N-L and type 2 L-R/R-N BAV morphologies had higher incidence of PVR. Larger studies evaluating different phenotypes of BAV are needed to confirm these findings.Clinical trial registrationClinicalTrials.gov Identifier: NCT03385915.
| S-EPMC7907039 | biostudies-literature