Mutation Analysis Of NEXN And JPH2 Genes In Families With Familial Atrial Fibrillation

Background:Atrial fibrillation is the most common arrhythmia encountered in clinical practice.It usually presents unstable and unpredictable activation of the atrium,resulting in atrial contraction asynchrony and irregular ventricular excitation.It has high incidence rate and mortality.With the acceleration of population aging,the prevalence of atrial fibrillation is expected to increase five times by 2050.In the past 20 years,significant progress has been made in the management of atrial fibrillation,but the burden of disease continues to increase.In terms of treatment,the available methods have many limitations,including the limited efficacy and significant side effects of antiarrhythmic drugs,as well as the recurrence and potential complications of atrial fibrillation ablation.Therefore,we need to better understand the mechanism of atrial fibrillation and its progress,so as to improve our understanding and ability to create and utilize new therapeutic approaches.Although the underlying mechanism of atrial fibrillation is very complex,many potential pathways and risk factors have been found.In addition to the known risk factors such as age,gender and basic heart disease,new risk factors such as heredity and environment are known by more and more people.Although most patients with atrial fibrillation have complications,such as hypertension,coronary artery disease or heart failure,many patients do not have the known risk factors mentioned above,which is called isolated atrial fibrillation.From the perspective of genetics,isolated atrial fibrillation can be divided into familial atrial fibrillation and non familial atrial fibrillation.Familial atrial fibrillation follows Mendelian inheritance and is closely related to gene variation.In 2005,genome wide association study(GWAS)technology was used to identify disease-related genetic loci.Until now,linkage and candidate gene sequencing methods are still the main methods to identify AF gene.Through genome-wide association studies,at least 30 genetic loci have been found to be associated with AF.through the study of human genetics and genetics,we can better understand the biological mechanism of AF.Objective:Second generation sequencing technology was used to screen the pathogenic genes and analyze the mutation sites in a family of patients with atrial fibrillation.Method:A total of 111 subjects were included,including 10 probands and their family members of three generations,and 101 healthy subjects.With the approval of the hospital ethics committee and the consent of the subjects,peripheral venous blood was collected.Firstly,genomic DNA was extracted from the peripheral blood of the proband.The exons and adjacent introns(50bp)of all human genes were captured by xgen ﹥ R exome research panel hybridization.The captured DNA was eluted and amplified,and sequenced by sequencing platform.The sequencing results were analyzed by bioinformatics method.After the suspicious pathogenic sites were found,Sanger sequencing method was used to verify the results in the family members and 101 healthy people.Polyphen2,mutationtaster and provean software were used to detect the function of mutated genes,and Swiss model software was used to analyze the three-dimensional structure model of protein before and after mutation.Result:1.Gene mutation was found in the proband by gene sequencing: NEXN c.919 C>A(p.P307T)and JPH2 c.1088G>A(p.R363H)。.2.The heterozygous mutation of nexn gene resulted in the change of base 919 from C to a,and the change of amino acid 307 from proline to threonine(p.p307t).Heterozygous variation of jph2 gene resulted in the change of base 1088 from G to a and the change of amino acid 363 from arginine to histidine(p.r363h).3.In addition to the proband,the rest of the family members were scanned with nexn gene and jph2 gene respectively.Among them,4 cases carried nexn gene mutation(i-1,II-2,II-7 and iii-4),2 cases carried jph2 gene mutation(i-1,II-9),No c.919 c > A(p.p307t)mutation of nexn gene and c.1088 g > A(p.r363h)mutation of jph2 gene were detected in proband’s wife(ii-4)and 100 healthy controls.4.The amino acid sequences of the regions where the two mutations were located were highly conserved.Polyphen2,mutationtaster and provean software predicted that the nexn gene heterozygous variation and jph2 gene heterozygous variation were harmful.Conclusion:Many members of the family carry the nexn c.919 c > A(p.p307t)heterozygous mutation and jph2 c.1088 g > A(p.r363h)heterozygous mutation.These two gene mutations are closely related to the occurrence of atrial fibrillation in members of the family,which may be the pathogenic gene mutation site of atrial fibrillation in the family.