MYH7 mutation identified by next-generation sequencing in three infant siblings with bi-ventricular noncompaction presenting with restrictive hemodynamics

A 17-month-old boy was referred to our institution due to syncope and heart failure. He had no known family history of heart disease or sudden cardiac death. Echocardiography revealed that both cardiac ventricles had a coarsely trabeculated and spongy appearance in posterior wall, lateral wall, apical segments, and right ventricle, suggestive of bi-ventricular noncompaction (Fig. 1A). Left ventricular ejection fraction (LVEF) was estimated at 51%, with normal left ventricle end-diastolic volume (110%), bi-atrial and right ventricular enlargement, moderate tricuspid regurgitation (velocity 5.0 m/sec), moderate mitral regurgitation, and no other congenital heart disease. E-wave deceleration time at the transmitral level was short (85 msec) with a high E/A ratio (2.1) (Fig. 1B), suggesting restrictive physiology. The ratio between the thickness of the noncompacted layer and the myocardial layer was 3.4:1.

We used the diagnosis criteria of NVM as follows: (1) The characteristic appearance of numerous, excessively prominent trabeculations and deep intertrabecular recesses on echocardiography. Two-layered appearance of the myocardium, with an increased noncompacted to compacted ratio >2.0. (2) Multiple deep intertrabecular recesses communicating with the ventricular cavity, as demonstrated by color Doppler imaging.

He was diagnosed with isolated bi-ventricular noncompaction with restrictive hemodynamics and severe pulmonary hypertension. He next underwent cardiac catheterization. Ventriculography showed a sponge-like layer in both ventricles. Left ventricular systolic pressure and end-diastolic pressure were 95 mmHg and 37 mmHg, respectively. Pulmonary artery pressures were elevated (systolic/diastolic/mean pressure: 61/21/39 mmHg). Mean pulmonary capillary wedge pressure and right atrial pressure were 35 and 10 mmHg, respectively. Pulmonary vascular resistance was 4.0 Wood Unit m². Although he was treated for heart failure, his clinical condition did not improve and he died of advanced heart failure at 2 years of age.

The second sibling, a female, was born when the proband (Case 1) was 21 months old. Echocardiography in the neonatal period showed bi-ventricular trabeculations in posterior wall, lateral wall, apical segments, and right ventricle (Fig. 1C, Supplementary Video S1a, b) and a depressed LVEF of 38%. She was diagnosed with isolated bi-ventricular noncompaction and gradually developed restrictive hemodynamics. E-wave deceleration time at the transmitral level was short (77 msec) with a high E/A ratio (2.2) (Fig. 1D), the ratio of early transmitral velocity to tissue Doppler lateral and septal mitral annular early diastolic velocity (E/e’) were 12.2 and 18.6, suggesting restrictive physiology, when she was 9 months old. Her parents hoped to pursue heart transplantation. She underwent cardiac catheterization at 3 years 3 months of age. Ventriculography showed a sponge-like layer in both ventricles (Supplementary Video S2a, S2b). Left ventricular systolic pressure and end-diastolic pressure were 64 mmHg and 15 mmHg, respectively. Pulmonary artery pressures were elevated (systolic/diastolic/mean pressure: 58/27/40 mmHg). Mean pulmonary capillary wedge pressure and right atrial pressure were 20 and 9 mmHg, respectively. Pulmonary vascular resistance was 8.6 Wood Unit m². She received medication for heart failure as an outpatient, including diuretics, an angiotensin-converting enzyme inhibitor, a ß-adrenergic blocker, and aspirin. However, when she was 4 years old, she suddenly went into cardiac arrest. Echocardiography revealed low echoic lesions in the right atrial and right ventricle, suggesting a thrombotic cause of cardiac arrest. She was resuscitated but developed hypoxic ischemic encephalopathy, which made her ineligible for heart transplantation. When she was 7 years old, she died of advanced heart failure.

The youngest sibling, a female, was born when Case 2 was 2 years 4 months old. Echocardiography in the neonatal period showed bi-ventricular trabeculations in posterior wall, lateral wall, apical segments, and right ventricle (Fig. 1E, F) and a depressed LVEF of 35%. She was diagnosed with isolated bi-ventricular noncompaction and gradually developed restrictive hemodynamics. Her heart failure rapidly progressed, and she died of advanced heart failure at 12 months of age. An autopsy was performed with her parents’ consent. Grossly, both ventricles showed coarse trabeculations (Fig. 2A, B). Microscopic examination revealed anastomosing endocardial trabeculations with thickened endocardial fibrosis accompanied by insufficient formation of cardiac muscle wall (Fig. 2C, D).