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Left ventricular noncompaction (LVNC) is characterized by prominent myocardial trabeculations and deep intertrabecular recesses, with variable clinical outcomes ranging from asymptomatic to heart failure and arrhythmia. Diagnostic criteria rely on imaging-defined noncompaction, but genetic testing can distinguish pathologic LVNC from a benign morphological trait. Meta-analysis of 35 studies including 2 271 LVNC patients demonstrated a pooled MIB1 mutation frequency of ~2% (n≈45 probands) across diverse cohorts, underscoring MIB1 as a recurrent disease gene (PMID:30980206).
In a multigenerational study, heterozygous nonsense (c.811T>G (p.Trp271Gly)) and missense MIB1 variants were identified in LVNC families by whole‐exome sequencing, co-segregating with disease in at least two kindreds and accompanied by cosegregating modifier alleles in ASXL3, APCDD1, TMX3, CEP192, and BCL7A (PMID:36325906). These variants comprise rare loss-of-function and deleterious missense changes, consistent with an autosomal dominant inheritance pattern with variable penetrance.
Functional studies in CRISPR-Cas9 engineered mouse models carrying orthologous Mib1 nonsense or missense alleles revealed that homozygous loss is embryonic lethal, whereas heteroallelic combination of a null and a myocardium-restricted conditional allele recapitulates the LVNC phenotype by echocardiography and cardiac magnetic resonance imaging. Human induced pluripotent stem cell–derived cardiomyocytes harboring patient MIB1 mutations exhibit increased proliferation and defective morphological and metabolic maturation, mirroring trabecular persistence in LVNC (PMID:36325906).
Mechanistically, MIB1 encodes an E3 ubiquitin ligase essential for Notch ligand endocytosis and receptor activation. Mouse loss-of-function mutants exhibit failure of Notch1 intracellular domain generation and downstream Hes5 expression, leading to aberrant cardiomyocyte differentiation. MIB1 cooperates with Neuralized-2 in Delta ubiquitylation and endocytic trafficking, establishing its central role in Notch-mediated cardiac morphogenesis (PMID:16061358; PMID:17003037).
No studies to date have refuted the MIB1–LVNC association, and aggregate data from population cohorts, family‐based sequencing, and functional modeling provide robust support. While additional segregation analyses and longitudinal clinical follow-up would strengthen penetrance estimates, current evidence satisfies ClinGen criteria for a Strong gene–disease relationship.
Key Take-home: MIB1 genetic testing should be integrated into LVNC diagnostic panels, as identification of pathogenic MIB1 variants informs prognosis, guides family screening, and enables mechanistic therapeutic exploration.
Gene–Disease AssociationStrongVariants in ~2% of 2271 LVNC probands and heterozygous MIB1 nonsense and missense mutations co-segregating in LVNC families; concordant functional in vivo and in vitro data Genetic EvidenceModerateMIB1 variants identified in ~2% of 2271 probands (PMID:30980206) and heterozygous MIB1 nonsense and missense alleles co-segregate in LVNC pedigrees (PMID:36325906) Functional EvidenceStrongMouse models recapitulate LVNC with orthologous Mib1 mutations by echocardiography and CMR, and human iPSC-CMs exhibit proliferation and maturation defects consistent with LVNC (PMID:36325906) |