PT - JOURNAL ARTICLE AU - Daoud, Hussein AU - Zhang, Dong AU - McMurray, Fiona AU - Yu, Andrea AU - Luco, Stephanie M AU - Vanstone, Jason AU - Jarinova, Olga AU - Carson, Nancy AU - Wickens, James AU - Shishodia, Shifali AU - Choi, Hwanho AU - McDonough, Michael A AU - Schofield, Christopher J AU - Harper, Mary-Ellen AU - Dyment, David A AU - Armour, Christine M TI - Identification of a pathogenic <em>FTO</em> mutation by next-generation sequencing in a newborn with growth retardation and developmental delay AID - 10.1136/jmedgenet-2015-103399 DP - 2016 Mar 01 TA - Journal of Medical Genetics PG - 200--207 VI - 53 IP - 3 4099 - http://jmg.bmj.com/content/53/3/200.short 4100 - http://jmg.bmj.com/content/53/3/200.full SO - J Med Genet2016 Mar 01; 53 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&gt;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.