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Haematologica 2018 Volume 103(12):2008-2015
Ferrata Storti Foundation
Red Cell Biology & its Disorders
The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2
Lisa G. Riley,1,2,* Matthew M. Heeney,3,4,* Joëlle Rudinger-Thirion,5
Magali Frugier,5 Dean R. Campagna,6 Ronghao Zhou,3 Gregory A. Hale,7
Lee M. Hilliard,8 Joel A. Kaplan,9 Janet L. Kwiatkowski,10,11 Colin A. Sieff,3,4 David P. Steensma,12,13 Alexander J. Rennings,14 Annet Simons,15
Nicolaas Schaap,16 Richard J. Roodenburg,17 Tjitske Kleefstra,15
Leonor Arenillas,18 Josep Fita-Torró,19 Rasha Ahmed,20 Miguel Abboud,20
Elie Bechara,21 Roula Farah,21 Rienk Y. J. Tamminga,22 Sylvia S. Bottomley,23 Mayka Sanchez,19,24,25 Gerwin Huls,26 Dorine W. Swinkels,27
John Christodoulou1,2,28,29,# and Mark D. Fleming3,6,13,#
*LGR and MMH contributed equally to this work. #JC and MDF contributed equally to this work as co-senior authors.
1Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, Australia; 2Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Australia; 3Dana Farber-Boston Children’s Center for Cancer and Blood Disorders, Boston, MA, USA; 4Department of Pediatrics, Harvard Medical School, Boston, MA, USA; 5Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg, France; 6Department of Pathology, Boston Children's Hospital, Boston, MA, USA; 7Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA; 8Division of Pediatric Hematology Oncology, University of Alabama at Birmingham, AL, USA; 9Levine Children's Hospital, Charlotte, NC, USA; 10The Children’s Hospital of Philadelphia, Division of Hematology, Philadelphia, PA, USA; 11University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 12Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, MA, USA; 13Harvard Medical School, Boston, MA USA; 14Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; 15Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands; 16Department of Hematology, Radboud University Medical Centre, Nijmegen, the Netherlands; 17Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Centre, Nijmegen, the Netherlands; 18Laboratorio Citología Hematológica, Servicio Patología, GRETNHE, IMIM Hospital del Mar Research Institute, Hospital del Mar, Barcelona, Spain; 19Iron 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; 20Department of Pediatrics and Adolescents, American University of Beirut Medical Center, Beirut, Lebanon; 21Department of Pediatrics, Saint George Hospital University Medical Center, Beirut, Lebanon; 22Beatrix Children’s Hospital, Department of Pediatric Hematology, University Medical Center Groningen, University of Groningen, the Netherlands; 23Department of Medicine, University of Oklahoma College of Medicine, Oklahoma City, OK, USA; 24Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain; 25BloodGenetics, S.L., Esplugues de Llobregat, Barcelona, Spain; 26Department of Hematology, University Medical Center Groningen, the Netherlands; 27Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, the Netherlands; 28Neurodevelopmental Genomics Research Group, Murdoch Childrens Research Institute, Melbourne, Australia and 29Department of Paediatrics, Melbourne Medical School, University of Melbourne, Australia
ABSTRACT
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 sequenc- ing. 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
Correspondence:
john.christodoulou@mcri.edu.au
Received: October 17, 2017. Accepted: July 12, 2018. Pre-published: July 19, 2018.
doi:10.3324/haematol.2017.182659
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