Determination of Genotype and Phenotypes in Pediatric Patients With Biventricular Noncompaction

Abstract

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC.

Methods and results: We recruited children with left ventricular noncompaction from Japanese multi-institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy-associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0-6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate (P=0.0009).

Conclusions: Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease-causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality-related cardiac phenotypes.

Keywords: biventricular noncompaction; congenital heart disease; dyskinesis; genetics; heart failure; left ventricular noncompaction.

Figure 1. Two‐dimensional echocardiogram showing prominent trabeculations and recesses in both ventricles.

Apical 4‐chamber view (A) enlarged apical 4‐chamber view (B), and parasternal long axis view (C). LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.

Figure 2. Flow chart of the included and excluded patients.

BiVNC indicates biventricular noncompaction; CHD, congenital heart disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; and RCM, restrictive cardiomyopathy.

Figure 3. Comparison of echocardiographic data among phenotypes.

A, LVEF, B, LVDD Z score, C, LVPW Z score, and D, LVPWC Z score. Reduced LVEF was more common in the groups with DCM and BiVNC than in other groups. BiVNC indicates biventricular noncompaction; CHD, congenital heart disease; DCM, dilated cardiomyopathy; LVEF, left ventricular ejection fraction; LVDD, left ventricular diastolic diameter; LVPW, left ventricular posterior wall; and LVPWC, compacted layer of the left ventricular posterior wall.

Figure 4. Regional analysis of LV hypertrabeculation and dyskinesis by echocardiogram.

Percentage represents the prevalence of LV hypertrabeculation (A) and frequency of LV dyskinesis (B). A prominent noncompacted layer and dyskinesis in the LV region were most frequently observed in the group with BiVNC. AW indicates anterior wall; BiVNC, biventricular noncompaction; CHD, congenital heart disease; DCM, dilated cardiomyopathy; LW, lateral wall; N/C, ratio of noncompacted to compacted layers; PW; posterior wall; and SW, septal wall.

Figure 5. Pathogenic gene distributions in each group with LVNC.

Distribution of pathogenic variants according to LVNC phenotypes (A) and the population of pathogenic variants (B). The group with BiVNC had a higher ratio of mitochondria‐ and development‐related gene variants than the other groups. BiVNC indicates biventricular noncompaction; CHD, congenital heart disease; DCM, dilated cardiomyopathy;and LVNC, left ventricular noncompaction.

Figure 6. RT‐PCR and splicing analysis of c.646G>A variant in the TAZ gene.

A–C, RT‐PCR of blood‐derived cDNA from controls and the patients (458, 495). A, Gene structure of TAZ and positions of multiple mutations. Arrows, positions of primers. B, C, Agarose gel electrophoresis. β‐actin served as the control gene. Splicing patterns were detected by RT‐PCR using the primer set indicated in (A). The TAZ‐specific band was barely detectable in the blood samples of patients (458, 495). The band detected in the blood samples of controls represented normal splicing. D–F, Minigene analysis based on pCl‐neo‐wt/mut vector. D, Schematic illustration of cloned vectors. (E) Electrophoresis results of transcript PCR products in HEK293T cell lines. The structure of amplicons I to III is depicted on the right. F, Sanger sequencing of PCR products. Intron 8 (117 bp) retention between exons 8 and 9 was detected. CMV indicates cytomegalovirus; HC. healthy control; M, DNA marker; and RT‐PCR, reverse transcription polymerase chain reaction

Figure 7. Event‐free survival in patients with LVNC subtypes.

A, According to cardiothoracic ratio on chest X‐ray (B) and according to hospitalization (C). The group with BiVNC had the worst survival rate among all groups. BiVNC indicates biventricular noncompaction; CHD, congenital heart disease; CTR, cardiothoracic ratio; and DCM, dilated cardiomyopathy.