Abstract Background Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. Methods We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo chromodomain helicase DNA-binding protein 4 (CHD4) proband, CHD4 M202I , with congenital heart defects. We engineered a patient-specific model of CHD4 M202I (mouse CHD4 M195I ). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4 M195I -mediated ventricular wall defects. Results CHD4 M195I/M195I mice developed biventricular hypertrabeculaion and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4 M195I hearts, and the excessive trabeculation was associated with accumulation of extracellular matrix (ECM) proteins and a reduction of ADAMTS1, an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4 M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4 M195I protein showed augmented affinity to endocardial BRG1. This enhanced affinity resulted in failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. Conclusions Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4 M195I can be attenuated by the administration of ADAMTS1. Clinical Perspective What Is New? A patient-specific mouse model of CHD4 M202I develops ventricular hypertrabeculation and dies at birth. Proliferation of cardiomyocytes is significantly enhanced in CHD4 M195 I mice. ADAMTS1 is significantly downregulated in CHD4 M195I mice. Close interaction between CHD4 M195I and BRG1 robustly and continuously represses Adamts1 transcription, which impairs ADAMTS1-mediated termination of trabeculation in the developing mutant heart. What Are the Clinical Implications? This study provides a unique mouse model of ventricular noncompaction cardiomyopathy that faithfully reflects human patients’ genetic condition without disturbing the target gene’s expression and localization. Transcriptional repression of ECM protease ADAMTS1 by CHD4-BRG1 interaction is detrimental to ventricular wall maturation; maintaining appropriate ADAMTS1 levels in the heart could be a promising therapeutic approach for treating ventricular noncompaction cardiomyopathy.

A Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1-mediated Trabeculation Cessation