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. 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.
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 humanTLR3, 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.
Authors: Paul A van der Zwaag; Jan D H Jongbloed; Maarten P van den Berg; Jasper J van der Smagt; Roselie Jongbloed; Hennie Bikker; Robert M W Hofstra; J Peter van Tintelen Journal: Hum Mutat Date: 2009-09 Impact factor: 4.878
Authors: Jeffrey A Towbin; April M Lowe; Steven D Colan; Lynn A Sleeper; E John Orav; Sarah Clunie; Jane Messere; Gerald F Cox; Paul R Lurie; Daphne Hsu; Charles Canter; James D Wilkinson; Steven E Lipshultz Journal: JAMA Date: 2006-10-18 Impact factor: 56.272
Authors: Ioannis Eleftherianos; Sungyong Won; Stanislava Chtarbanova; Barbara Squiban; Karen Ocorr; Rolf Bodmer; Bruce Beutler; Jules A Hoffmann; Jean-Luc Imler Journal: Proc Natl Acad Sci U S A Date: 2011-06-30 Impact factor: 11.205
Authors: Arun Sharma; Caleb Marceau; Ryoko Hamaguchi; Paul W Burridge; Kuppusamy Rajarajan; Jared M Churko; Haodi Wu; Karim I Sallam; Elena Matsa; Anthony C Sturzu; Yonglu Che; Antje Ebert; Sebastian Diecke; Ping Liang; Kristy Red-Horse; Jan E Carette; Sean M Wu; Joseph C Wu Journal: Circ Res Date: 2014-07-11 Impact factor: 17.367
Authors: Derek E Neilson; Mark D Adams; Caitlin M D Orr; Deborah K Schelling; Robert M Eiben; Douglas S Kerr; Jane Anderson; Alexander G Bassuk; Ann M Bye; Anne-Marie Childs; Antonia Clarke; Yanick J Crow; Maja Di Rocco; Christian Dohna-Schwake; Gregor Dueckers; Alfonso E Fasano; Artemis D Gika; Dimitris Gionnis; Mark P Gorman; Padraic J Grattan-Smith; Annette Hackenberg; Alice Kuster; Markus G Lentschig; Eduardo Lopez-Laso; Elysa J Marco; Sotiria Mastroyianni; Julie Perrier; Thomas Schmitt-Mechelke; Serenella Servidei; Angeliki Skardoutsou; Peter Uldall; Marjo S van der Knaap; Karrie C Goglin; David L Tefft; Cristin Aubin; Philip de Jager; David Hafler; Matthew L Warman Journal: Am J Hum Genet Date: 2009-01 Impact factor: 11.025
Authors: Ray E Hershberger; Joann Lindenfeld; Luisa Mestroni; Christine E Seidman; Matthew R G Taylor; Jeffrey A Towbin Journal: J Card Fail Date: 2009-03 Impact factor: 5.712
Authors: Peter D Stenson; Matthew Mort; Edward V Ball; Katy Shaw; Andrew Phillips; David N Cooper Journal: Hum Genet Date: 2014-01 Impact factor: 4.132
Authors: Aziz Bousfiha; Leïla Jeddane; Waleed Al-Herz; Fatima Ailal; Jean-Laurent Casanova; Talal Chatila; Mary Ellen Conley; Charlotte Cunningham-Rundles; Amos Etzioni; Jose Luis Franco; H Bobby Gaspar; Steven M Holland; Christoph Klein; Shigeaki Nonoyama; Hans D Ochs; Eric Oksenhendler; Capucine Picard; Jennifer M Puck; Kathleen E Sullivan; Mimi L K Tang Journal: J Clin Immunol Date: 2015-10-07 Impact factor: 8.317
Authors: Alain van Mil; Geerthe Margriet Balk; Klaus Neef; Jan Willem Buikema; Folkert W Asselbergs; Sean M Wu; Pieter A Doevendans; Joost P G Sluijter Journal: Cardiovasc Res Date: 2018-12-01 Impact factor: 10.787
Authors: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Tomoya Kitani; Sang-Ging Ong; Chi Keung Lam; June-Wha Rhee; Joe Z Zhang; Angelos Oikonomopoulos; Ning Ma; Lei Tian; Jaecheol Lee; Melinda L Telli; Ronald M Witteles; Arun Sharma; Nazish Sayed; Joseph C Wu Journal: Circulation Date: 2019-05-21 Impact factor: 29.690
Authors: Amy R Kontorovich; Nihir Patel; Arden Moscati; Felix Richter; Inga Peter; Enkhsaikhan Purevjav; Simina Ramona Selejan; Ingrid Kindermann; Jeffrey A Towbin; Michael Bohm; Karin Klingel; Bruce D Gelb Journal: JACC Basic Transl Sci Date: 2021-07-26