Analysis Of Clinical Phenotype And Genetic Etiology Of A Family With Pulmonary Atresia

Objective With the rapid development of next-generation sequencing technology(NGS)in recent years and its widespread application in clinical testing,especially the application of whole exome sequencing(WES)in the clinical diagnosis of genetic diseases,a large number of genetic diseases caused by genes and mutations were discovered.Based on the clinical analysis,this study intends to use WES to sequence and analyze the genetic cause of a family with three generations of pulmonary atresia in order to find the genetic cause of this family and provide reference for further treatment and genetic counseling.Methods The clinical diagnosis of the family of pulmonary atresia is strictly diagnosed by cardiac color Doppler ultrasound.Both patients were treated in our hospital with a good prognosis,and both were confirmed as pulmonary artery atresia during the operation;the genetic etiology was studied by collecting peripheral blood from all members of the family and extracting genetic DNA,sequencing the probands and their parents with all exome sequecing,and using Sanger to confirm the relative mutations of the remaining relatives.SIFT,Polyphen-2 and conservative analysis were used to analyze the pathogenicity of the mutation,and the detected pathogenic mutations were classified according to the American ACMG mutation classification guidelines.Sanger sequencing was used to verify and analyze the pathogenic candidate mutations in other family members with blood samples available.Results Both the clinical symptoms and color Doppler ultrasound support the clinical diagnosis of the probands of this family as pulmonary atresia,and all of them have undergone pulmonary atresia repair surgery,which was confirmed to be pulmonary atresia during operation;the core families have detected a total of 17059 probands by exome sequencing.There are 97103 mutation sites in each gene,and 26 reference mutations were obtained through the filtering analysis of the family,database and prediction software.Finally,the c.2804 of the BMPR2 gene was obtained by combining the clinical phenotype and sanger sequencing detection of the family members and co-segregation analysis of the family C> T(p.A935V)mutation is a possible genetic cause of this pulmonary artery atresia family.According to the US ACMG variant classification guidelines,the variant can be classified as a suspected pathogenic variant.Conclusion Congenital pulmonary atresia have a variety of pathogenic genes.Whole exome sequencing technology has great potential in exploring the genetic etiology.The c.2804C>T(p.A935V)mutation of the BMPR2 gene is the cause of congenital pulmonary artery atresia Suspected disease-causing mutation.