Genetic Screening And Genotype-phenotype Analysis In A Chinese Cohort With Mitral Valve Prolapse

Background:Mitral valve prolapse(MVP)is a common cardiovascular disease which was defined as a late systolic murmur associated with "billowing" or prolapse of one or both of the mitral leaflets into the left atrium,with or without mitral regurgitation.Myxomatous is the most important pathologic type of MVP and is the most common pathologic cause of isolated mitral regurgitation requiring surgical repair.Non-syndromic myxomatous MVP has autosomal and X-linked dominant patterns of inheritance.DCHS1 and FLNA have been identified as disease-causing genes.Non-syndromic MVP is also related to TNS1 and LMCD1.The development of syndromic MVP is associated with FBN1.However,most foreign studies have only screened 1-3 genes.Currently,there is no research which explores myxomatous MVP pathogenic mutations in China.The incidence of known mutations in MVP population is unknown.Purpose:This study was aimed to screen the pathogenic mutations of non-syndromic myxomatous MVP patients,evaluate the status of known mutations in Chinese myxomatous MVP population,and preliminarily investigate the relationship between genotype and phenotype.Providing evidence for early diagnosis and accurate treatment.Methods:From 2011 to 2017,60 unrelated Chinese patients with myxomatous MVP were recruited prospectively in the study.DNA samples isolated from the peripheral blood of the index cases were screened for pathogenic genes.Fifty-one known and suspected pathogenic genes were analyzed using targeted region sequencing in next-generation sequencing.Variants with a minor allele frequency<1%,which were predicted damaging by bioinformatics analysis and absent from healthy controls,were defined as rare variants.Rare variants were validated by Sanger sequencing.Patients were given a comprehensive clinical evaluation and follow-up.Results:Of the recruited 60 myxomatous MVP patients,28(46.7%)were detected with 37 rare variants.Six patients carried more than 1 variant.These rare variants were distributed among 7 genes(TNS1,ELN,MYH6,FBN1,ACAN,TGFBR2 and COL5A1),7 in TNS1,3 in ELN,7 in MYH6,9 in FBN1,9 in ACAN,and 1 each in TGFBR2 and COL5A1,respectively.All rare variants were missense,novel and absent from the healthy controls.Seven patients(11.7%)were detected with rare variants of the 4 associated genes.The rare variants carriers had lower left ventricular ejection fraction(LVEF)than the non-carriers(62.6±5.5%versus 66.3± 4.6%,P = 0.007).Patients with more than 1 rare variant experienced shorter disease course(4.9 ± 9.4 versus 33.0 ± 45.6 months,P =0.000)than those without.No significant difference was observed between rare variants carriers and non-carriers with respect to mortality during follow-up(mean length,16.7±15.2 months).Conclusions:This study finds some rare variants in myxomatous MVP,which are associated with dysregulation of multiple pathways involving extracellular matrix,transforming growth factor β(TGF-β)signaling,collagen,elastic fibers and muscle contractile function involved in mitral valve regurgitation.Carrying rare variants may indicate a decrease in the left ventricular systolic function and carrying multi rare variants may be associated with disease progression.Background:Mitral valve prolapse(MVP)was defined as a late systolic murmur associated with"billowing" or prolapse of one or both of the mitral leaflets into the left atrium,with or without mitral regurgitation.MVP is a common disorder,afflicting 2%to 3%of the general population.MVP is expected to affect more than 176 million people worldwide.Myxomatous MVP is the most important pathologic type of MVP and is the most common pathologic cause of isolated mitral regurgitation requiring surgical repair.There is limited information on long-term outcomes of mitral valve repair for mitral regurgitation caused by different degrees of myxomatous degeneration.Purpose:The aim of the study was to explore the clinical characteristics of MVP patients and compare postoperative prognosis results of patients with advanced and mild/moderate myxomatous mitral valve degeneration.This degeneration classification was based on ultrasonic and pathological results.Methods:From August 2008 to February 2015,we identified 130 patients who underwent mitral valve repair for mitral regurgitation in Fuwai hospital.All patients were pathologically diagnosed as myxomatous degeneration.We analyzed clinical features retrospectively.According to ultrasonic and pathological examination results,patients were divided into advanced(25 patients)and mild/moderate(105 patients)groups.Patients were given a comprehensive clinical evaluation and follow-up.The clinical data of 2 groups were statistically analyzed.Results:The clinical symptoms of MVP patients included dyspnea[58.5%(76/130)],chest distress and pain[56.9%(74/130)],and palpitations[37.7%(49/130)].Posterior leaflet prolapse accounts for 74%(96/130)patients.Kaplan-Meier analysis showed that survival differed significantly between advanced and mild/moderate myxomatous mitral valve degeneration(MVD)groups(76.0 ± 9.7%vs 95.0 ± 5.4%at 8 years,P<0.001).The univariate predictors of mortality were advanced myxomatous degeneration,recurrent mitral regurgitation and early series(surgeries before 2011).Kaplan-Meier analysis also showed that the advanced MVD group had lower freedom from moderate or severe mitral regurgitation rate compared with the mild/moderate MVD group(50.5 ± 10.2%versus 77.4 ± 4.5%at 7 years,P = 0.003).Multivariable Cox analysis revealed advanced myxomatous degeneration(hazard ratio[HR]2.120,confidence interval[CI]1.013 to 4.437,P = 0.046)and residual mitral regurgitation(HR 3.376,95%CI 1.614 to 7.063,P=0.001)as independent predictors of recurrent moderate or severe mitral regurgitation.A total of 25 patients(19.2%)had persistent atrial fibrillation after repair.In multivariate analysis,advanced myxomatous degeneration(odds ratio[OR]6.767,95%CI 2.153 to 21.276,P = 0.001)and preoperative left atrial diameter(OR 1.119,95%CI 1.045 to 1.198,P = 0.001)was found to be an independent predictor of postoperative persistent atrial fibrillation.Conclusions:The long-term outcomes of mitral valve repair in patients with advanced MVD are poorer than in those with mild/moderate MVD.Advanced myxomatous degeneration is an independent predictor of recurrent moderate or severe mitral regurgitation and postoperative persistent atrial fibrillation in MVD patients performing repair,which deserves more attention before and after surgery.