title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York. Electronic address: sbelkaya@rockefeller.edu.
authors.forename: Serkan
authors.initials: S
authors.lastname: Belkaya
authors.affiliation: 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.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Kontorovich
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.affiliation: 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.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mulero-Navarro
authors.affiliation: Centre de Référence Malformations Cardiaques Congénitales Complexes-M3C, Paris Descartes University, Sorbonne Paris Cité, AP-HP, Necker Hospital for Sick Children, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Bajolle
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Josowitz
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Quint
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Boucherit
authors.affiliation: Service de Pédiatrie Générale, CHU Réunion, site GHSR, La Reunion, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Stoven
authors.affiliation: Pediatric Cardiology and Congenital Heart Disease Department, Cardiovascular Louis-Pradel Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Di Filippo
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: 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.
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Centre de Référence Malformations Cardiaques Congénitales Complexes-M3C, Paris Descartes University, Sorbonne Paris Cité, AP-HP, Necker Hospital for Sick Children, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: 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.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics*; D016022:Case-Control Studies; D029822:Enterovirus B, Human / Q000502:physiology*; D005260:Female; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D009205:Myocarditis / Q000235:genetics* / Q000821:virology; D032383:Myocytes, Cardiac / Q000821:virology; D050794:STAT1 Transcription Factor / Q000235:genetics*; D051196:Toll-Like Receptor 3 / Q000235:genetics*
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3
keywords: cardiomyocytes; children; genetics; immunity; sequencing; virus