title: Neonatal encephalocardiomyopathy caused by mutations in VARS2.
abstract: VARS2 encodes a mitochondrial aminoacyl-tRNA-synthetase. Mutations in VARS2 have recently been identified as a cause of mitochondrial encephalomyopathy in three individuals. However, clinical information remained scarce. Exome sequencing lead us to identify compound heterozygous pathogenic VARS2 variants in a boy presenting with severe lactic acidosis, hypertrophic cardiomyopathy, epilepsy, and abnormalities on brain imaging including hypoplasia of corpus callosum and cerebellum as well as a massive lactate peak on MR-spectroscopy. Studies in patient-derived fibroblasts confirmed the functional relevance of the identified VARS2 variants. Our report expands the phenotypic spectrum associated with this rare mitochondrial defect, in that VARS2 deficiency may also cause severe neonatal presentations with cardiac involvement and structural brain abnormalities.
authors: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors: Fabian
authors: F
authors: Baertling
authors: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.
authors: Bader
authors: B
authors: Alhaddad
authors: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors: Annette
authors: A
authors: Seibt
authors: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors: Sonja
authors: S
authors: Budaeus
authors: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors: Thomas
authors: T
authors: Meitinger
authors: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors: Tim M
authors: TM
authors: Strom
authors: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors: Ertan
authors: E
authors: Mayatepek
authors: Medical Faculty, Department of Diagnostic and Interventional Radiology, University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors: Jörg
authors: J
authors: Schaper
authors: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors: Holger
authors: H
authors: Prokisch
authors: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors: Tobias B
authors: TB
authors: Haack
authors: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany. Felix.distelmaier@med.uni-duesseldorf.de.
authors: Felix
authors: F
authors: Distelmaier
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D009154:Mutation; D014637:Valine-tRNA Ligase / Q000235:genetics*
chemical_list: D006680:HLA Antigens; C070977:VARS2 protein, human; D014637:Valine-tRNA Ligase
keywords: Aminoacyl tRNA synthtetase; Cardiomyopathy; Mitochondrial disease; OXPHOS; VARS2