Study On The Correlation Between NAP1L1 D349E Somatic Variant And Hypertrophic Cardiomyopathy And Risk Gene Somatic Variant In Aortic Dissectio

BackgroundHypertrophic cardiomyopathy is a primary myocardial disease characterized by asymmetrical hypertrophy of the ventricular wall.The pathogenesis of hypertrophic cardiomyopathy is unknown in about 25%-30%patients,especially sporadic patients.Somatic mutations have been demonstrated to be the main etiology of many sporadic cardiovascular diseases but its role in hypertrophic cardiomyopathy(HCM)remains unclear.This study aims to assesse the prevalence and function of somatic NAP1L1 D349E in HCM patients.MethodsSeventy-one sporadic patients with HCM from Fuwai Hospital were recruited as the discovery cohort.After germline mutations analysis,twenty sporadic patients without causative germline mutations were included into somatic mutation calling.The replication cohort contained forty-nine sporadic HCM patients from the First Affiliated Hospital of Xi’an Jiaotong University who was found to be negative of causative germline mutations in previous studies.Droplet digital PCR were performed in both cohorts.In silico tools including AlphaFold2,SIFT,PolyPhen2 were used to analyze the pathogenicity of mutations,and followed by experiments to varify the pathogenicity.WES of cardiac tissue from 27 heart transplants or donors were used as negative control.ResultsThe results showed that 7/20 in the discovery cohort and 12/49 in the replication cohorts carried somatic mutation NAP1L1 D349E.Patients with NAP1L1 D349E were in higher NYHA class(p=0.006796,tau=0.608 in the discovery cohort and P=2.589e-05,tau=0.5890825 in the replication cohort).None of controls carried this mutation.Polyphen2 suggested that the mutation was likely pathogenic,and AlphaFold2 suggested that the mutation affected local secondary structure of the NAP1L1.Through Co-immunoprecipitation,we demonstrated that alternation of NAP1L1 D349E weakened the binding of Nap111 to Ube2o,and then decreased the ubiquitination and degradation of uL2.Thus,NAP1L1 D349E led to UPS dysfunction,which was considered to contribute to cardiomyocyte hypertrophy.ConclusionThis study firstly addressed the prevalence of somatic mutation NAP1L1 D349E in sporadic HCM patients without causative germline mutations.Patients with NAP1L1 D349E were in higher NYHA class.Our findings support a causative role of somatic NAP1L1 mutation D349E in sporadic HCM.BackgroundThoracic aortic dissection(TAD)is a fatal disease,and more than half of patients with thoracic aortic dissection in developed countries still do not receive effective treatment before death.Somatic mutations have already been demonstrated to be the main etiology in many cardiovascular diseases but its role in TADremains unclear.AimWe aimed to study the proportion and function of somatic mutations in aortic dissection-related genes in patients with thoracic aortic dissection.MethodsThirty-four patients and fourteen patients were included as the discovery cohort and replication cohort,respectively.WES and RNA sequencing were performed to identify the function of somatic mutations.GSEA,ssGSEA and cluster analysis were applied to generalize the transcriptome landscape of dissecting aortic tissues.Mutational signature was also investigated.FindingsNineteen of thirty in the discovery cohort and six of fourteen in the replication cohort carried pathogenic or likely pathogenic(P/LP)somatic mutations in TAD related genes.None of these mutations were observed in controls.Cluster analysis showed that patients with germline and somatic COL1A2 mutations shared the same burden of COL1A2 loss of function.Patients carrying P/LP somatic and germline mutations of FBN1 significantly deviated from others in ssGSEA enrichment score of FBN1associated GO and pathways.Significant contribution of mutational signature SBS6 were found in eighteen patients,which is associated with disturbed DNA mismatch repair.ConclusionSomatic mutations occur at a higher rate in aortic dissection and may confer functions similar to germline mutations.