Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Abstract

BACKGROUND Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon- (IFN) α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES We evaluated the hypothesis that human genetic factors might underlie AVM in previously healthy children. METHODS We tested the role of TLR3-IFN immunity utilizing human-induced pluripotent stem cell-derived cardiomyocytes. We then performed whole exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral etiologies. RESULTS We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to coxsackievirus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous, but not heterozygous, rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections.

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

“…Moreover, very recently, a higher incidence of recessive mutations in genes implicated in cardiomyopathy (including BAG3, DSP, PKP2, RYR2, SCN5A and TNNI3) has been demonstrated in patients with acute myocarditis [40]. Also, the potential importance of cytoskeletal and membrane proteins in the pathogenesis of myocarditis is emerging [41].…”

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

“…This is a lower ratio of de novo variants than previously reported. 2 [36][37][38] Here, we showed absence of the TNNI3 protein in heart tissue of patients with homozygous TNNI3 mutation. Moreover, we suggest impaired TNNI isoform switching in the postnatal heart indicated by increased TNNI1 (fetal isoform) protein and mRNA levels in both patients.…”

“…This study identified two patients with either DCM (1‐II:1, p.Arg69Alafs*) or LVNC (2‐II:3, c.24+2T>A) carrying homozygous TNNI3 loss‐of‐function variants. It is known that heterozygous TNNI3 variants cause DCM, HCM, and RCM; however, homozygous mutation of TNNI3 is a rare event, and to our knowledge so far, three homozygous TNNI3 cases have been described: the missense variant p.Ala2Val (DCM), the synonymous variant c.G150A (p.Lys50Lys) causing aberrant splicing of TNNI3 mRNA (DCM), and a genomic deletion comprising the TNNI3 exon 8 as well as the entire TNNT2 gene (DCM) . Here, we showed absence of the TNNI3 protein in heart tissue of patients with homozygous TNNI3 mutation.…”

Severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: Results from the prospective multicenter registry “MYKKE”

“…27,28 On the other hand, de novo mutations or genetic predisposition may determine the course of myocarditis. 29,30 The immunological response might be gender-dependent and differ in various age groups. The fulminant course with acute cardiac deterioration in very young children might be caused either by an incomplete or by an overshooting immune system.…”