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Abstract
Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.
Highlights
Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal; in the absence of coronary artery disease, valvular heart disease, hypertension, or congenital heart disease sufficient to cause the observed myocardial abnormality [1].In pediatric cardiomyopathy registries, the incidence of dilated cardiomyopathy (DCM) have been reported to be 1/140 000–1/170 000 [2, 3], the clinical course is often severe [2]
Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood
After a severe clinical course with decline of cardiac function, there was a need of external left ventricular assist as a bridge to heart transplantation
Summary
Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal; in the absence of coronary artery disease, valvular heart disease, hypertension, or congenital heart disease sufficient to cause the observed myocardial abnormality [1].In pediatric cardiomyopathy registries, the incidence of DCM have been reported to be 1/140 000–1/170 000 [2, 3], the clinical course is often severe [2]. Dilated cardiomyopathy is the most frequent underlying diagnosis leading to pediatric heart transplantation [3]. DCM may be caused by congenital heart disease, coronary anomalies, arrhythmias, myocarditis, myopathies, or metabolic cardiomyopathy, some cases remain idiopathic [2, 4, 5]. Familial dilated cardiomyopathy (FDC) is a rare cause of DCM, especially in childhood [2]. Dilated Cardiomyopathy is characterized primarily by left ventricular dilatation and impaired systolic function and is one of the leading causes of heart failure with high morbidity and mortality. Familial dilated cardiomyopathy is identified in 20–48% of cases with DCM [4], less common in pediatric DCM [2]. If the pedigree can reveal more than one individual with DCM are denoted as FDC [4, 10]
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