A nonsense variant in FBN1 caused autosomal dominant Marfan syndrome in a Chinese family: a case report.

BACKGROUND: Marfan syndrome (MFS) is a common autosomal dominant inherited disease, and the occurrence rate is around 0.1-0.2‰. The causative variant of FNB1 gene accounts for approximately 70-80% of all MFS cases. In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene. This finding extended the variant spectrum of the FBN1 gene and will provide a solution for patients to bear healthy offspring by preimplantation genetic testing or prenatal diagnosis. CASE PRESENTATION: The patient was treated due to tachycardia during excitement in a hospital. Echocardiography showed dilatation of the ascending aorta and main pulmonary artery, mitral regurgitation (mild), tricuspid regurgitation (mild), and abnormal left ventricular filling. Electrocardiograph showed sinus rhythm. In addition, flutters of shadows in front of his eyes and vitreous opacity were present in the patient. Genomic DNA was extracted from peripheral blood samples from members of the family and 100 unrelated controls. Potential variants were screened out by next-generation sequencing and confirmed by MLPA & Sanger sequencing. Real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the relative mRNA quantitation in the patient. A heterozygous nonsense variant c.3217G > T of the FBN1 gene, which resulted in p. Glu1073Term, was identified in both patients. Only wild type bases were found in the cDNA sequence of the patient. Real-time fluorogenic quantitative PCR results showed that the relative expression level of FBN1 cDNA in the patient was only about 21% compared to that of normal individuals. This variant c.3217G > T of the FBN1 gene introduces a Stop codon in the cb-EGF12 domain. We speculated that a premature translational-termination codon (PTC) was located in the mRNA and the target mRNA was disintegrated through a process known as nonsense-mediated mRNA decay (NMD), which led to a significant decrease of the fibrillin-1 protein, eventually causing clinical symptoms in the patient. CONCLUSIONS: In this study, we found a heterozygous c.3217G > T (p.Glu1073*) nonsense variant in the FBN1 gene, which eventually led to Marfan syndrome in a Chinese family.

Inter-ethnic differences in valve morphology, valvular dysfunction, and aortopathy between Asian and European patients with bicuspid aortic valve.

Background: Transcatheter aortic valve replacement (TAVR) has been shown safe and feasible in patients with bicuspid aortic valve (BAV) morphology. Evaluation of inter-ethnic differences in valve morphology and function and aortic root dimensions in patients with BAV is important for the worldwide spread of this therapy in this subgroup of patients. Comparisons between large European and Asian cohorts of patients with BAV have not been performed, and potential differences between populations may have important implications for TAVR. Aim: The present study evaluated the differences in valve morphology and function and aortic root dimensions between two large cohorts of European and Asian patients with BAV. Methods and results: Aortic valve morphology was defined on transthoracic echocardiography according to the number of commissures and raphe: type 0 = no raphe and two commissures, type 1 = one raphe and two commissures, type 2 = two raphes and one commissure. Aortic stenosis and regurgitation were graded according to current recommendations. For this study, aortic root dimensions were manually measured on transthoracic echocardiograms at the level of the aortic annulus, sinus of Valsalva (SOV), sinotubular junction (STJ), and ascending aorta (AA). Of 1427 patients with BAV (45.2 ± 18.1 years, 71.9% men), 794 (55.6%) were Europeans and 633 (44.4%) were Asians. The groups were comparable in age and proportion of male sex. Asians had higher prevalence of type 1 BAV with raphe between right and non-coronary cusps than Europeans (19.7% vs. 13.6%, respectively; P < 0.001), whereas the Europeans had higher prevalence of type 0 BAV (two commissures, no raphe) than Asians (14.5% vs. 6.8%, respectively; P < 0.001). The prevalence of moderate and severe aortic regurgitation was higher in Europeans than Asians (44.2% vs. 26.8%, respectively; P < 0.001) whereas there were no differences in BAV with normal function or aortic stenosis. After adjusting for demographics, comorbidities, and valve function, the dimensions of the aortic annulus [mean difference 1.17 mm/m2, 95% confidence interval (CI) 0.96-1.39], SOV (mean difference 1.86 mm/m2, 95% CI 1.47-2.24), STJ (mean difference 0.52 mm/m2, 95% CI 0.14-0.90) and AA (mean difference 1.05 mm/m2, 95% CI 0.57-1.52) were significantly larger among Asians compared with Europeans. Conclusions: This large multicentre registry reports for the first time that Asians with BAV showed more frequently type 1 BAV (with fusion between right and non-coronary cusp) and have larger aortic dimensions than Europeans. These findings have important implications for prosthesis type and size selection for TAVR.

Bicuspid aortic valve: inter-racial difference in frequency and aortic dimensions.

OBJECTIVES: The objective of this study was to examine the similarities and differences in Caucasian (C) and African-American (AA) patients with bicuspid aortic valve (BAV) with respect to morphology, severity of aortic stenosis/insufficiency, and aortic dilation. BACKGROUND: BAV is a common congenital valve abnormality, accounting for a large number of valve replacements. METHODS: A total of 229 patients with the diagnostic code BAV were identified retrospectively from our computerized adult echocardiographic database, which consists of 91,896 studies performed at the University of Chicago Medical Center from 1998 to 2009, representing 40,878 patients. Of those, 183 patients with BAV were included in this retrospective BAV single-center cohort study and reanalyzed with a comprehensive assessment of aortic dimensions, aortic valve morphology and function, clinical cardiovascular risk factors, and patient characteristics. RESULTS: Of the 183 patients with BAV, 138 were C and 45 were AA. Our echocardiographic database encompasses approximately 65% AA, 31% C, and 4% other races, for an estimated frequency of BAV in AA patients of 0.17% and a frequency in C patients of 1.1% (p = 0.001). There were no significant inter-racial differences regarding sex, height, weight, hyperlipidemia, diabetes, tobacco use, cardiac medications, and left ventricular ejection fraction. The AA cohort was older (age 50 ± 17 years vs. 43 ± 17 years, p < 0.05) and had a higher prevalence of hypertension (51% vs. 24%, p < 0.05). After adjusting for comorbidities, aortic dimensions were larger in C (C vs. AA: annulus, 2.4 ± 0.4 vs. 2.1 ± 0.4 cm; sinuses of Valsalva, 3.4 ± 0.7 vs. 3.1 ± 0.6 cm; sinotubular junction, 3.0 ± 0.6 vs. 2.6 ± 0.5 cm; and ascending aorta, 3.5 ± 0.7 vs. 3.2 ± 0.5 cm; all p values <0.05). CONCLUSIONS: This is the first study to report racial differences among patients with BAV with reduced aortic dimensions in AA patients despite the presence of more risk factors, suggestive of marked heterogeneity in the BAV population and indicating race as a potential disease modifier in BAV.

Cardiovascular manifestations of Takayasu arteritis and their relationship to the disease activity: analysis of 204 Korean patients at a single center.

Takayasu's arteritis (TA) is primary vasculitis. Cardiac involvements in TA is due to the consequences of the vascular lesions as well as the primary pathology of the heart. The disease activity of TA is known to influence the prognosis of TA. We hypothesized that the cardiovascular involvement of TA is related to the disease activity. We evaluated the cardiovascular manifestations of TA, and we assessed their relation to the disease activity of TA. Two hundred four patients were diagnosed with TA from September, 1994 to March, 2009 according to the diagnostic criteria of the 1990 American College of Rheumatology. Their clinical features and the laboratory, angiographic and echocardiographic findings were retrospectively reviewed. The group with active disease activity was defined as satisfying one of the following criteria: i) an elevated ESR or CRP level, ii) thickened arterial wall with mural enhancement on CT or MR angiography, and iii) carotidynia at the time of the initial diagnosis. One hundred thirty nine patients (69.2%) were classified as the active group. The cardiovascular signs and symptoms were not generally different between the active and inactive groups. The active TA patients had more frequent involvement of the ascending aorta and the aortic arch and its main branches than did the inactive group. The active group showed a higher incidence of significant aortic valve regurgitation and pulmonary hypertension, and a higher level of NT-proBNP. These findings suggest that disease activity plays an important role for the cardiovascular manifestations of TA. The TA patients with higher activity have more cardiovascular morbidity compared to the TA patients with low disease activity.

Repeat cardiac surgery in a Jehovah's Witness patient with thrombocytopenia.

Complex cardiac surgery in Jehovah's Witness patients can be challenging, especially if it is a reoperation and the patient has a preexisting bleeding disorder. We operated on a patient who was declined for percutaneous aortic valve replacement and who required repeat surgery for aortic valve repeat replacement and root repair. In addition to being of Jehovah's Witness faith, the patient had chronic thrombocytopenia. We describe our strategy in managing this situation.

Prevalence estimation and follow-up of aortic regurgitation subjects in a Norwegian Sami population.

OBJECTIVES: To estimate the prevalence of aortic regurgitation (AR) in the Sami population and its association with ankylosing spondylitis and HLA-B27. DESIGN: A random sample from two Norwegian Sami communities was invited to participate in a health survey. Echocardiography was carried out for 84% of the 416 invited. Logistic regression analysis was used to estimate the odds ratios (OR). The AR persons entered a clinical follow-up programme. RESULTS: Altogether 28 subjects had AR. Weighted overall prevalence of AI was 8.8%. OR of AR for ankylosing spondylitis, age and HLA-B27 were 7.4 (95% CI: 1, 1-49, 0), 1.08 (95% CI, 1, 03-2, 14) and 1.8 (95% CI: 0, 6-5, 4), respectively. CONCLUSIONS: The prevalence of AR was 8.8% in the Sami populations in Northern Norway, which is comparable to that reported in other populations; however, data from other populations are sparse. AR was strongly associated with ankylosing spondylitis, but not with HLA-B27 antigen. The progress rate of AR seems to be low; no clinically significant hemodynamic changes were noted during the 14-to-17-year follow-up programme.

Epidemiology of pure valvular regurgitation in the large middle-aged African American cohort of the Atherosclerosis Risk in Communities study.

BACKGROUND: There are limited data on the prevalence and the clinical and echocardiographic correlates of pure valvular regurgitation in African Americans despite the higher rates of cardiovascular disease in this group. PURPOSE: The Jackson, Mississippi, site of the Atherosclerosis Risk in Communities study provides a unique opportunity to study mitral regurgitation (MR), tricuspid regurgitation (TR), and aortic regurgitation (AR) in this population. METHODS: There were 2285 participants who were available for analysis. The prevalence rates of MR, TR, and AR by severity were calculated for participants aged 50 to 59, 60 to 69, and > or = 70 years. Multivariable regression analyses were conducted to determine clinical and echo variables associated with the presence of MR, TR, and AR. RESULTS: Mild or greater MR and TR were present in 14.7% and 17.2% of participants, respectively. Aortic regurgitation was present in 15.6% of participants. In the multivariable regression model, MR was independently associated with age, sex, lower body mass index (BMI), systolic blood pressure, left atrial size, left ventricular (LV) diastolic diameter, and low LV ejection fraction. Tricuspid regurgitation was independently associated with age, sex, lower BMI, high-density lipid, left atrial size, and lower relative wall thickness. Aortic regurgitation was independently associated with age, sex, lower BMI, systolic blood pressure, LV diastolic diameter, LV hypertrophy, and low LV ejection fraction. CONCLUSION: In this middle-aged African Americans cohort, the prevalence of mild to greater MR and TR was similar to that seen in other cohorts; however, AR was more prevalent. Several cardiovascular risk factors and echo parameters were identified as independent correlates of valvular regurgitation.

Prevalence and correlates of aortic regurgitation in American Indians: the Strong Heart Study.

OBJECTIVES: We sought to determine the prevalence and correlates of aortic regurgitation (AR) in a population-based sample group. BACKGROUND: Concern over induction of AR by weight loss medication highlights the importance of assessing the prevalence and correlates of AR in unselected patient groups. METHODS: Aortic regurgitation was assessed by color flow Doppler echocardiography in 3,501 American Indian participants age 47 to 81 years during the second Strong Heart Study. RESULTS: Mild (1+) AR was present in 7.3%, 2+ AR in 2.4% and 3+ to 4+ AR in 0.3% of participants, more frequently in those > or =60 years old than in those <60 years old (14.4% vs. 5.8%, p<0.001); AR was unrelated to gender. Compared with participants without AR, those with mild AR had a lower body mass index (p<0.004) and higher systolic pressure (p<0.003). Participants with AR had larger aortic root diameters (3.6+/-0.4 vs. 3.4+/-0.4 cm, p<0.001), higher creatinine levels (1.3+/-1.3 vs. 1.0+/-1.0 mg/dl, p<0.001) and higher urine albumin/creatinine levels (3.6+/-2.3 vs. 3.3+/-2.0 log, p<0.001), as well as higher prevalences of aortic stenosis (AS) or mitral stenosis (MS) (p<0.001). Regression analysis showed that AR was independently related to older age and larger aortic roots (p<0.0001), AS and absence of diabetes (p = 0.002), MS (p = 0.003) and higher log urine albumin/creatinine (p = 0.005). CONCLUSIONS: Aortic regurgitation occurred in 10% of a sample group of middle-aged to older adults and was related to older age, larger aortic root diameter, aortic and mitral stenosis and albuminuria. There was no association of AR with being overweight and a negative association of AR with diabetes.