| Part 1:Screening of Pathogenic Genes Mutation Associated with Bicuspid Aortic Valve in a Chinese FamilyBackgroundThe bicuspid aortic valve(BAV)is one of the most common types of congenital heart disease,affecting approximately 0.5 to 2 percent of the overall population.Genetic studies showed that its genetic pattern is consistent with autosomal dominant inheritance with incomplete penetrance.Family pedigrees studies have found that the prevalence of a first-degree relatives of BAV patients is approximately 9 to 10 percent,and the heritability of BAV is about 89%,indicating a strong genetic component to the development of this congenital defect.The pathogenesis of BAV was once thought to be related to genes,environment,hemodynamics and other factors.In recent years,with the development of high-throughput sequencing technology,the diagnosis and understanding of BAV has improved.and BAV-related gene loci including NOTCH1,ACTA2,UFD1L,S AMD6,EGFR,NKX2-5,TEX26,TGFBR2,AXIN1,ENG,PDIA2,GATA5,NOS3,GATA4.Pathogenic gene mutations associated with BAV affect the formation of endocardial cushion through corresponding molecular signaling pathways,such as the formation of outflow tracts and endocardium mesenchymal transition,crest cell migration,and extracellular mesenchymal remodeling.AimsThis study intended to screen pathogenic mutations in a three-generation BAV family to explore the genetic molecular pathogenicity of BAV by Whole-exon sequencing and Sanger sequencing.Subjects and methodsSix members from a three-generation pedigree with BAV were included in this study.Data collection was conducted including medical history,comorbidities,results of physical examination,electrocardiogram,echocardiogram,chest X-ray and biochemical test.Genome Wide sequencing was performed in two patients and one normal control in the same pedigree.Sanger sequencing was used to validate co-segregation of the candidate variant with the disease in all affected family members.One hundred unrelated healthy control samples were also subjected to variant examination.ResultsThe pedigree investigation showed that the proband’s father was diagnosed with BAV by echocardiography at the age of 30.He received aortic valve replacement surgery due to severe aortic valve insufficiency and left ventricular enlargement at 60 years old and postoperative pathology confirmed BAV.The proband was identified BAV by ultrasound examination at age of 20.None variant filtered from target region sequencing was included.Two patients including proband and her father and one healthy control received whole exome sequencing.A novel candidate variant,c.1684G>A(p.Va1562Ile),was detected in PRDM16 by whole exome sequencing.It was validated to segregate in affected members of the family by Sanger sequencing,and to be absent in 100 unrelated healthy control samples.ConclusionA novel disease-causing variant related to BAV was identified by high-throughput sequencing in our study.Functional study is needed to validate its pathogenicity and how it affects the development of aortic valve in the future.Gene sequencing can discover potential genes related with BAV and improve the understanding of pathogenic mechanism.Part 2:Clinical Characteristics,Treatments and Outcomes of Bicuspid Aortic Valves Combined with Infective EndocarditisBackgroundBicuspid aortic valve(BAV)can be an independent disease,or accompanied by other congenital heart diseases or aortic diseases.BAV patients are also at high risk for a variety of cardiovascular comorbidities,including ascending aorta dilation,aortic dissection,and infective endocarditis(IE).IE is an infectious disease,as infections caused by pathogenic microorganisms at endocardium or heart valves,which has a high risk of morbidity and mortality and requires timely intervention.Currently,few studies had focused on patients with BAV combined IE.The incidence of BAV with IE is about 2%to 3%,which is lower than other comorbidities.Combining IE on the basis of BAV can cause significant changes of heart valve during a short period of time,which in turn leads to a progressive decline in cardiac function,and also indicating poorer prognosis.The clinical characteristics,treatment strategy and early-term outcomes of BAV with IE remain unclear.AimsThis study intended to retrospectively reveal the clinical characteristics,treatment strategies and early-term outcomes of patients diagnosed with BAV and IE,and also to compare those characteristics with patients with isolated BAV.The results will provide comprehensive vital data for the clinical diagnosis and treatment for patients with BAV and IE.Subjects and methodsAll adult patients with BAV or BAV with IE who were admitted at Fuwai Hospital from January 2013 to December 2018 were included in the analysis.Isolated adult BAV patients were randomly selected by admission time and treatment strategy.The inclusion criteria including(1)BAV confirmed by echocardiography,and/or surgical pathology,(2)IE diagnosis made by modified Duke criteria;(3)Patient age≥18 years.Patients data including baseline data,basic diseases,clinical manifestations,echocardiographic results,in-hospital treatments,and short-term outcomes were collected via standardized case report form by two independent clinicians.We analyzed and compared all data between two groups of patients by SPSS 25.0.ResultsBAV with IE patients were younger(38±11years vs.49±13 years,P<0.001),had fewer comorbidities including hypertension,coronary heart disease and diabetes than isolated BAV patients.The symptoms were more serious and heart function was relatively worse than isolated BAV patients.Male predominance was also observed.Echocardiography showed that the average of left ventricular diastolic dimension,aortic annulus diameter of BAV with IE patients were larger compared with isolated BAV patients(65.3±8.8mm vs.56.4±11.4mm,P<0.001;25.4±3.3mm vs.24.0±3.3mm,P=0.002).Severe regurgitation was more frequently found in BAV with IE patients than isolated BAV patients(91.2%vs.49.0%,P<0.001),while BAV with IE patients were less common with aortic stenosis(16.2%vs.50.0%,P<0.001).Blood and node culture found that Streptococcus was the main pathogens in BAV with IE patients.The surgery was performed in 64(94.1%)BAV with IE patients without postoperative reoperation or death.Four patients received medical treatment,and 1 patient(1.5%)died for multi-organ dysfunction.One hundred and ninety-two(94.1%)isolated BAV patients received operation,and 2(1%)patients died during hospitalization.Six patients underwent reoperation for bleeding or perivalvular leakage.There was no significantly statistical difference in mortality and reoperation rates between the two groups.ConclusionCompared with isolated BAV,BAV with IE patients were younger,male predominant had fewer comorbidities and higher incidence of aortic valve regurgitation.Surgery remained the main treatment choice for patients with BAV with IE,and the early-term outcome was comparable with isolated BAV. |
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