title: Inherited balanced translocation t(9;17)(q33.2;q25.3) concomitant with a 16p13.1 duplication in a patient with schizophrenia.
abstract: We report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5 Mbp microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important.
authors.affiliation: SA Pathology, Women's and Children's Hospital, Adelaide, South Australia 5006, Australia.
authors.forename: Tod
authors.initials: T
authors.lastname: Fullston
authors.forename: Bronte
authors.initials: B
authors.lastname: Gabb
authors.forename: David
authors.initials: D
authors.lastname: Callen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Erica
authors.initials: E
authors.lastname: Woollatt
authors.forename: Sharon
authors.initials: S
authors.lastname: Bain
authors.forename: Hilger H
authors.initials: HH
authors.lastname: Ropers
authors.forename: Matt
authors.initials: M
authors.lastname: Cooper
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Kim
authors.initials: K
authors.lastname: Carter
authors.forename: Assen
authors.initials: A
authors.lastname: Jablensky
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D000328:Adult; D000483:Alleles; D002885:Chromosomes, Human, Pair 16; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005190:Family; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056916:Segmental Duplications, Genomic; D014178:Translocation, Genetic
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins