title: A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.
abstract: The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non-related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey.
authors.forename: Ahmet O
authors.initials: AO
authors.lastname: Çağlayan
authors.affiliation: Division of Genetics, Department of Pediatrics, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tüysüz
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Coşkun
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quon
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Akdes S
authors.initials: AS
authors.lastname: Harmancı
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Baranoski
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Burçin
authors.initials: B
authors.lastname: Baran
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: E Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Department of Genetics, Center for Human Genetics and Genomics and Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilgüvar
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Katsuhito
authors.identifier: http://orcid.org/0000-0002-3606-532X
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D001706:Biopsy; D002675:Child, Preschool; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D003241:Consanguinity; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense; D010641:Phenotype; D059467:Transcriptome
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human