RT Journal Article SR Electronic T1 Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 200 OP 207 DO 10.1136/jmedgenet-2015-103399 VO 53 IS 3 A1 Hussein Daoud A1 Dong Zhang A1 Fiona McMurray A1 Andrea Yu A1 Stephanie M Luco A1 Jason Vanstone A1 Olga Jarinova A1 Nancy Carson A1 James Wickens A1 Shifali Shishodia A1 Hwanho Choi A1 Michael A McDonough A1 Christopher J Schofield A1 Mary-Ellen Harper A1 David A Dyment A1 Christine M Armour YR 2016 UL http://jmg.bmj.com/content/53/3/200.abstract AB 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.