title: Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.
abstract: Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband's affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.
authors: Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy.
authors: Fabiola
authors: F
authors: Ceroni
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Nuala H
authors: NH
authors: Simpson
authors: 1] Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands [2] Donders Institute for Brain, Cognition & Behaviour, Nijmegen, Netherlands.
authors: Clyde
authors: C
authors: Francks
authors: Guy's & St Thomas NHS Foundation Trust, Newcomen Children's Neurosciences Centre, St Thomas' Hospital, London, UK.
authors: Gillian
authors: G
authors: Baird
authors: School of Psychological Sciences, The University of Manchester, Manchester, UK.
authors: Gina
authors: G
authors: Conti-Ramsden
authors: Speech and Hearing Sciences, Queen Margaret University, Edinburgh, UK.
authors: Ann
authors: A
authors: Clark
authors: Departments of Child & Adolescent Psychiatry & Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Kings College London, London, UK.
authors: Patrick F
authors: PF
authors: Bolton
authors: University Child Health and DMDE, University of Aberdeen, Aberdeen, UK.
authors: Elizabeth R
authors: ER
authors: Hennessy
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Peter
authors: P
authors: Donnelly
authors: Illumina Cambridge Ltd., Chesterford Research Park, Little Chesterford, Essex, UK.
authors: David R
authors: DR
authors: Bentley
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Hilary
authors: H
authors: Martin
authors: Institute of Neuroscience and Health and Society, Newcastle University, Newcastle, UK.
authors: Jeremy
authors: J
authors: Parr
authors: 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK [2] NIHR Biomedical Research Centre, Oxford and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Alistair T
authors: AT
authors: Pagnamenta
authors: Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy.
authors: Elena
authors: E
authors: Maestrini
authors: Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy.
authors: Elena
authors: E
authors: Bacchelli
authors: 1] Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands [2] Donders Institute for Brain, Cognition & Behaviour, Nijmegen, Netherlands.
authors: Simon E
authors: SE
authors: Fisher
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Dianne F
authors: DF
authors: Newbury
mesh_terms: D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017384:Sequence Deletion; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C510122:DOCK4 protein, human; D020690:GTPase-Activating Proteins; D012333:RNA, Messenger; C000598506:zinc finger protein 277, human; D010450:Endopeptidases; C425070:IMMP2L protein, human