The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2
Lisa G. Riley,
Matthew M. Heeney,
Joëlle Rudinger-Thirion,
Magali Frugier,
Dean R. Campagna,
Ronghao Zhou,
Gregory A. Hale,
Lee M. Hilliard,
Joel A. Kaplan,
Janet L. Kwiatkowski,
Colin A. Sieff,
David P. Steensma,
Alexander J. Rennings,
Annet Simons,
Nicolaas Schaap,
Richard J. Roodenburg,
Tjitske Kleefstra,
Leonor Arenillas,
Josep Fita-Torró,
Rasha Ahmed,
Miguel Abboud,
Elie Bechara,
Roula Farah,
Rienk Y. J. Tamminga,
Sylvia S. Bottomley,
Mayka Sanchez,
Gerwin Huls,
Dorine W. Swinkels,
John Christodoulou,
Mark D. Fleming
Affiliations
Lisa G. Riley
Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, Australia;Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Australia
Matthew M. Heeney
Dana Farber-Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA;Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Joëlle Rudinger-Thirion
Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France
Magali Frugier
Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France
Dean R. Campagna
Department of Pathology, Boston Children’s Hospital, Boston, MA, USA
Ronghao Zhou
Dana Farber-Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA
Gregory A. Hale
Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
Lee M. Hilliard
Division of Pediatric Hematology Oncology, University of Alabama at Birmingham, AL, USA
Joel A. Kaplan
Levine Children’s Hospital, Charlotte, NC, USA
Janet L. Kwiatkowski
The Children’s Hospital of Philadelphia, Division of Hematology, Philadelphia, PA, USA;University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Colin A. Sieff
Dana Farber-Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA;Department of Pediatrics, Harvard Medical School, Boston, MA, USA
David P. Steensma
Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA USA
Alexander J. Rennings
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands
Annet Simons
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands
Nicolaas Schaap
Department of Hematology, Radboud University Medical Centre, Nijmegen, the Netherlands
Richard J. Roodenburg
Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Centre, Nijmegen, the Netherlands
Tjitske Kleefstra
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands
Leonor Arenillas
Laboratorio Citología Hematológica, Servicio Patología, GRETNHE, IMIM Hospital del Mar Research Institute, Hospital del Mar, Barcelona, Spain
Josep Fita-Torró
Iron metabolism: regulation and disease group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Campus Can Ruti, Carretera de Can Ruti, Cami de les Escoles, Badalona, Spain
Rasha Ahmed
Department of Pediatrics and Adolescents, American University of Beirut Medical Center, Beirut, Lebanon
Miguel Abboud
Department of Pediatrics and Adolescents, American University of Beirut Medical Center, Beirut, Lebanon
Elie Bechara
Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon
Roula Farah
Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon
Rienk Y. J. Tamminga
Beatrix Children’s Hospital, Department of Pediatric Hematology, University Medical Center Groningen, University of Groningen, the Netherlands
Sylvia S. Bottomley
Department of Medicine, University of Oklahoma College of Medicine, Oklahoma City, OK, USA
Mayka Sanchez
Iron metabolism: regulation and disease group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Campus Can Ruti, Carretera de Can Ruti, Cami de les Escoles, Badalona, Spain;Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain;BloodGenetics, S.L., Esplugues de Llobregat, Barcelona, Spain
Gerwin Huls
Department of Hematology, University Medical Center Groningen, the Netherlands
Dorine W. Swinkels
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, the Netherlands
John Christodoulou
Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, Australia;Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Australia;Neurodevelopmental Genomics Research Group, Murdoch Childrens Research Institute, Melbourne, Australia;Department of Paediatrics, Melbourne Medical School, University of Melbourne, Australia
Mark D. Fleming
Dana Farber-Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA;Department of Pathology, Boston Children’s Hospital, Boston, MA, USA;Harvard Medical School, Boston, MA USA
YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.
