PMC8042379_01
Pedigree analysis and sequencing results. (A) Pedigree of the proband (arrow) and his family members with heterozygous ACTN2 variant. Gray symbol indicates that the presence of ACTN2 variant was not determined. (B) Sanger sequencing confirmed a novel missense mutation (c.668T>C; p.Leu223Pro) in ACTN2, which was of paternal origin. It is highlighted in the red box. (C) Sequence alignment of the conserved cytoplasmic domain of the ACTN2 protein in multiple vertebrate species. Protein sequence of the Leu223Pro residue is highly conserved across the compared species. It is highlighted in the red box.
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F1
The proband's grandfather (I-1 in Figure 1A) died at the age of 35 years due to gastric cancer, and his cardiac history was unknown. The proband's 74-year-old grandmother (I-2 in Figure 1A) did not have any cardiac disease except for hypertension. The father's brother (II-3 in Figure 1A) had no clinical symptoms, lived in another area, and did not agree to be tested. The proband's mother was completely normal through birth to adolescent and showed no skeletal muscle myopathies or cardiac symptoms and was not investigated.
Echocardiography and cardiac magnetic resonance imaging (cMRI) in the proband (III-2). (A-C) Echocardiography and Color Doppler showed dilated left ventricle chamber and prominent trabeculation and flow within the deep intertrabecular recesses. (D-F) cMRI revealed that the non-compacted to compacted ratio >=2 and severely dilated biventricular myocardium that was compatible with dilated LVNC. (G) Proband's electrocardiogram demonstrated sinus arrhythmia and non-specific intraventricular conduction delay.
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F2
The proband underwent transthoracic echocardiography (TTE), which showed a non-compacted myocardium with a dilated cardiomyopathy phenotype such as left ventricular end-diastolic dimension (LVEDD) 60 mm, interventricular septal dimension (IVS) 8.2 mm, left ventricular ejection fraction (LVEF) 25% (Figures 2A-C). Cardiac magnetic resonance imaging (cMRI) revealed LVNC with dilated cardiomyopathy (Figures 2D-F). Holter monitoring showed sinus arrhythmia and non-specific intraventricular conduction delay, as well as rare atrial premature contraction (Figure 2G). He did not complain of any skeletal muscle symptoms, and serum muscle enzyme levels were normal.
Echocardiography and cardiac magnetic resonance imaging (cMRI) in the proband's father (II-1) (upper and middle panel) and sister (III-1) (lower panel). (A-C) Echocardiography showed left ventricular hypertrophy and apical echogenic mass or dense trabeculation and apical septal aneurysm (arrow) in the proband's father. (D-F) cMRI determined dense trabeculation and focal apical septal aneurysm that considered as hypertrophic LVNC in the proband's father. (G-I) Echocardiography in proband's sister showed normal left ventricular function and geometry except for prominent trabeculation of left ventricle that diagnosed with isolated LVNC in the proband's sister.
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F3
His TTE showed an echogenic mass or trabeculation and a LVEF of 35% with aneurysmal changes in the apical wall (Figures 3A-C). These findings could be considered as the hypertrophic phenotype of LVNC (Figures 3D-F). The proband's 18-year-old sister (III-1 in Figure 1A) did not have any symptoms; however, her TTE revealed LVNC with normal LVEF, which was consistent with isolated LVNC (Figures 3G-I).
PMC8042379_02
Pedigree analysis and sequencing results. (A) Pedigree of the proband (arrow) and his family members with heterozygous ACTN2 variant. Gray symbol indicates that the presence of ACTN2 variant was not determined. (B) Sanger sequencing confirmed a novel missense mutation (c.668T>C; p.Leu223Pro) in ACTN2, which was of paternal origin. It is highlighted in the red box. (C) Sequence alignment of the conserved cytoplasmic domain of the ACTN2 protein in multiple vertebrate species. Protein sequence of the Leu223Pro residue is highly conserved across the compared species. It is highlighted in the red box.
fped-09-609389-g0001.jpg
PMC8042379_02_fped-09-609389-g0001.jpg
F1
The proband's grandfather (I-1 in Figure 1A) died at the age of 35 years due to gastric cancer, and his cardiac history was unknown. The proband's 74-year-old grandmother (I-2 in Figure 1A) did not have any cardiac disease except for hypertension. The father's brother (II-3 in Figure 1A) had no clinical symptoms, lived in another area, and did not agree to be tested. The proband's mother was completely normal through birth to adolescent and showed no skeletal muscle myopathies or cardiac symptoms and was not investigated.