title: Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay.
abstract: BACKGROUND
  A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations.
  
  
  METHODS
  We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents.
  
  
  RESULTS
  We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity.
  
  
  CONCLUSIONS
  Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Fiona
authors.initials: F
authors.lastname: McMurray
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Luco
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Vanstone
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Jarinova
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Carson
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Wickens
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Shifali
authors.initials: S
authors.lastname: Shishodia
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Hwanho
authors.initials: H
authors.lastname: Choi
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Armour
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
keywords: Developmental Delay; FTO; Neonatal Intensive Care Unit; Next Generation Sequencing