A New Genetic Variant of Unknown Clinical Significance in a Case of Familiar Left Ventricular Noncompaction Cardiomyopathy

Objectives: Noncompaction cardiomyopathy is a rare congenital cardiomyopathy, characterized by a thin, compacted epicardial layer and an extensive noncompacted endocardial layer in the left ventricle. The clinical manifestations vary greatly including life-threatening ventricular tachycardia and embolic events.

Case Report: We present a 6-year-old female patient, who was transferred to our clinic due to recurrent syncopes and nonfebrile seizures despite β-blocker therapy. Family history showed sudden cardiac death of three siblings at the age of 3, 6, and 13 years with parents being consanguineous. Echocardiography showed increased fractions of noncompacted left ventricular myocardium with normal biventricular function (noncompacted-to-compacted ratio 2:1). MRI showed reduced fractions of compacted myocardium from the apical to midventricular parts of the left ventricle. Right ventricular biopsy confirmed the diagnosis of noncompaction cardiomyopathy. Subsequent evaluation of the autopsy of one deceased sister showed noncompaction cardiomyopathy, respectively. Genetic testing revealed heterozygous variants of the genes PDLIM3 (p.Q209X) and TTN (p.G2008S), coding for intramyocardial proteins with an unknown clinical significance. Due to the family history and recurrent syncopes, implantation of an extracardiac ICD was performed. During 21-month follow-up, no further syncopes or seizures occurred. Size and function of the left ventricle are normal. Screening of the asymptomatic family members included echocardiography and MRI as well as a genetic testing. In case of suspicious results, we performed heart catheter. One brother showed a suspicious echocardiography. MRI and right ventricular biopsy did not show signs of noncompaction cardiomyopathy. He is heterozygous for the TTN mutation, and wild type for the PDLIM3 gene. Of the other siblings, one sister is heterozygous for both mutations, one sister and the mother are heterozygous for the PDLIM3 mutation, and the father is heterozygous for the TTN mutation.

Conclusion: In the genesis of left ventricular noncompaction, genetic inheritance plays an important role. It arises in 30 to 50% of patients and new mutations may help identify patients at risk. We found a new genetic variant in a case of familiar left ventricular noncompaction cardiomyopathy. Especially, the PDLIM3 mutation, which might lead to a truncated protein or nonsense-mediated mRNA decay by a premature stop codon could be of significance in our case.