title: Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions.
abstract: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk.
  
  
  
  We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD).
  
  
  
  We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10(-7); OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21).
  
  
  
  Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Maria
authors.identifier: 0000-0002-5156-7539
authors.initials: M
authors.lastname: Tropeano
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Howley
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK Individual Differences, Language and Cognition Lab, Department of Developmental and Educational Psychology, University of Seville, Seville, Spain.
authors.forename: C Ellie
authors.initials: CE
authors.lastname: Wilson
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Joo Wook
authors.initials: JW
authors.lastname: Ahn
authors.affiliation: Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK.
authors.forename: Clodagh M
authors.initials: CM
authors.lastname: Murphy
authors.affiliation: Population Diagnostics, Inc., Melville, New York, USA.
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Eis
authors.affiliation: Population Diagnostics, Inc., Melville, New York, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Hatchwell
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Richard J B
authors.initials: RJ
authors.lastname: Dobson
authors.affiliation: Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK.
authors.forename: Dene
authors.initials: D
authors.lastname: Robertson
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Melita
authors.initials: M
authors.lastname: Irving
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Annelise
authors.initials: A
authors.lastname: Nehammer
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Debbie
authors.initials: D
authors.lastname: Spain
authors.affiliation: Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Pitts
authors.affiliation: UCD School of Psychology, University College Dublin, Dublin, Ireland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bramham
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Curran
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Vassos
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Caroline Mackie
authors.initials: CM
authors.lastname: Ogilvie
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Discovery Neuroscience Research, Eli Lilly and Company Ltd, Erl Wood Manor, Windlesham, Surrey, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Molecular Genetics, McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Grainne M
authors.initials: GM
authors.lastname: McAlonan
authors.affiliation: Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Declan G
authors.initials: DG
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006130:Growth Disorders / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D000071439:Pseudoautosomal Regions / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors
keywords: Copy number variation; Dosage-sensitive gene; Enhancer; Female; Neurodevelopment