Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Serkan Belkaya; Amy R Kontorovich; Minji Byun; Sonia Mulero-Navarro; Fanny Bajolle; Aurelie Cobat; Rebecca Josowitz; Yuval Itan; Raphaelle Quint; Lazaro Lorenzo; Soraya Boucherit; Cecile Stoven; Sylvie Di Filippo; Laurent Abel; Shen-Ying Zhang; Damien Bonnet; Bruce D Gelb; Jean-Laurent Casanova

doi:10.1016/j.jacc.2017.01.043

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

J Am Coll Cardiol. 2017 Apr 4;69(13):1653-1665. doi: 10.1016/j.jacc.2017.01.043.

Authors

Serkan Belkaya¹, Amy R Kontorovich², Minji Byun³, Sonia Mulero-Navarro⁴, Fanny Bajolle⁵, Aurelie Cobat⁶, Rebecca Josowitz⁴, Yuval Itan³, Raphaelle Quint³, Lazaro Lorenzo⁶, Soraya Boucherit⁷, Cecile Stoven⁸, Sylvie Di Filippo⁹, Laurent Abel¹⁰, Shen-Ying Zhang¹⁰, Damien Bonnet⁵, Bruce D Gelb⁴, Jean-Laurent Casanova¹¹

Affiliations

¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York. Electronic address: sbelkaya@rockefeller.edu.
² Departments of Pediatrics and Genetics and Genomic Sciences, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
⁴ Departments of Pediatrics and Genetics and Genomic Sciences, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
⁵ Centre de Référence Malformations Cardiaques Congénitales Complexes-M3C, Paris Descartes University, Sorbonne Paris Cité, AP-HP, Necker Hospital for Sick Children, Paris, France.
⁶ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
⁸ Service de Pédiatrie Générale, CHU Réunion, site GHSR, La Reunion, France.
⁹ Pediatric Cardiology and Congenital Heart Disease Department, Cardiovascular Louis-Pradel Hospital, Hospices Civils de Lyon, Lyon, France.
¹⁰ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France; Pediatric Immunology-Hematology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute, The Rockefeller University, New York, New York.

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: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children.

Methods: We tested the role of TLR3-IFN immunity using 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 causes.

Results: We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus 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 (homozygous or compound heterozygous) 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 in children.

Keywords: cardiomyocytes; children; genetics; immunity; sequencing; virus.

MeSH terms

Cardiomyopathies / complications
Cardiomyopathies / genetics*
Case-Control Studies
Enterovirus B, Human / physiology*
Female
Host-Pathogen Interactions / genetics
Humans
Induced Pluripotent Stem Cells
Male
Myocarditis / genetics*
Myocarditis / virology
Myocytes, Cardiac / virology
STAT1 Transcription Factor / genetics*
Toll-Like Receptor 3 / genetics*

Substances

STAT1 Transcription Factor
STAT1 protein, human
TLR3 protein, human
Toll-Like Receptor 3

Abstract

MeSH terms

Substances

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