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Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay
  1. Hussein Daoud1,
  2. Dong Zhang2,
  3. Fiona McMurray3,
  4. Andrea Yu1,
  5. Stephanie M Luco1,
  6. Jason Vanstone4,
  7. Olga Jarinova1,
  8. Nancy Carson1,
  9. James Wickens2,
  10. Shifali Shishodia2,
  11. Hwanho Choi2,
  12. Michael A McDonough2,
  13. Christopher J Schofield2,
  14. Mary-Ellen Harper3,
  15. David A Dyment1,4,
  16. Christine M Armour1
  1. 1Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  2. 2Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK
  3. 3Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  4. 4Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  1. Correspondence to Drs Hussein Daoud and Christine M Armour, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1; hdaoud{at}, carmour{at}


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.

Conclusion 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.

  • FTO
  • Developmental Delay
  • Next Generation Sequencing
  • Neonatal Intensive Care Unit

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