Screening And Identification Of Pathogenic Genes In Two Dilated Cardiomyopathy Families

Objective: Cardiomyopathy is a group of myocardial diseases associated with myocardial and cardiac muscle dysfunction,and dilated cardiomyopathy(DCM)is the most common form of cardiomyopathy.DCM is characterized by left ventricle or bilateral ventricular dilatation with myocardial systolic dysfunction.The prognosis of DCM is poor,comparable to malignant tumors,and the 5-year survival rate is about 45%.DCM is the third leading cause of congestive heart failure and the most common cause of heart transplantation.Recent studies have shown that familial dilated cardiomyopathy(FDCM)is associated with genetic mutations,and 20 to 35 percent of patients with DCM have genetic characteristics.This study investigated two FDCM families,and whole exome sequencing analysis were conducted,expecting to find the new pathogenic gene or locus of DCM and trying to build the corresponding animal models to study pathogenic mechanism.Methods: Two families were analyzed to study the genetics of the dilated cardiomyopathy.Family 1 was a family with sinus bradycardia,and family 2 was a family with a intermarriage.Based on the patient’s telling and relevant heart examination on other family members,6 female patients and no male patients were found in family 1.Whole exome sequencing were conducted on the two patients(Ⅱ: 5,Ⅲ: 11).There were three patients in the family 2,genetic analysis were conducted on the proband and other family members,and the whole exome sequencing was conducted in four specimens(Ⅲ:3、Ⅲ:4、Ⅳ:1、Ⅳ:5)from the family.Further functional study of new genes or mutations were conducted.Results: The proband(Ⅱ:5)of family 1 was diagnosed with DCM accompanied with sinus bradycardia.Among other family members,all of the performance of sinus bradycardia were women.The results of whole exome sequencing showd that there was a new heterozygous mutation site on the gene of lamin gene(LMNA)in family 1.Sanger sequencing of all other members we could collected in the family further confirmed that the LMNA mutation(c.T686 C,p.I229T)was the pathogenic mutation site.Moreover,mitochondrial sequencing analysis of the other three female patients showed that there was no co-separation of mutation at the site.In family 2,Ⅲ:3 andⅢ:4 were cousins and they got married.The proband Ⅳ:1 was dignosed with DCM,and other patients were Ⅳ:3 and Ⅳ:5.The results of whole exome sequencing showed that there was a new mutation gene BICD2(c.G2429A: p.R.810H),which had never been proposed as pathogenic gene of DCM before.Sanger sequencing of all other members we could collected confirmed the conclusion.Conclusions: This study was the first time to find gene mutation of LMNA in the family of DCM with sinus bradycardia.Therefore,this study enlarged the mutation spectrum of LMNA gene.In addition,this study found a BICD2 homozygous mutation(c.G2429A:p.R810H)in a family of DCM with intermarriage and the inheritance pattern was autosomal recessive inheritance.This study expanded the bank of pathogenic gene of DCM,providing reference for the similar genetic counseling.