title: A t(3;9)(q25.1;q34.3) translocation leading to OLFM1 fusion transcripts in Gilles de la Tourette syndrome, OCD and ADHD.
abstract: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology; however, finding of candidate genes is hampered by its genetic heterogeneity and the influence of non-genetic factors on disease pathogenesis. We report a case of a male patient with GTS, obsessive compulsive disorder, attention-deficit/hyperactivity-disorder, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 (OLFM1) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. In addition, one of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. The translocation described is thus a unique event, but further studies in larger cohorts are required to elucidate involvement of OLFM1 in GTS pathogenesis.
authors.affiliation: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Linea
authors.initials: L
authors.lastname: Melchior
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Lars Riff
authors.initials: LR
authors.lastname: Jensen
authors.affiliation: Tourette Clinic, Department of Pediatrics, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Groth
authors.affiliation: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Lusine
authors.initials: L
authors.lastname: Nazaryan
authors.affiliation: Tourette Clinic, Department of Pediatrics, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark.
authors.forename: Nanette Mol
authors.initials: NM
authors.lastname: Debes
authors.affiliation: Tourette Clinic, Department of Pediatrics, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Skov
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors.forename: Gangcai
authors.initials: G
authors.lastname: Xie
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Brøndum-Nielsen
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Andreas Walter
authors.initials: AW
authors.lastname: Kuss
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. Electronic address: zeynep.tumer@regionh.dk.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D015897:Comorbidity; D003718:Denmark; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000453:epidemiology / Q000235:genetics*; D017354:Point Mutation; D005879:Tourette Syndrome / Q000453:epidemiology / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C081451:olfactomedin
keywords: Fusion transcripts; Microscopically balanced translocation; Neuropsychiatric disorder.; OLFM1; Tourette syndrome