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Original article
Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions
  1. Maria Tropeano1,2,
  2. Deirdre Howley3,4,5,
  3. Matthew J Gazzellone6,7,
  4. C Ellie Wilson3,4,8,
  5. Joo Wook Ahn9,
  6. Dimitri J Stavropoulos10,11,
  7. Clodagh M Murphy3,4,
  8. Peggy S Eis12,
  9. Eli Hatchwell12,
  10. Richard J B Dobson1,
  11. Dene Robertson4,
  12. Muriel Holder5,
  13. Melita Irving5,
  14. Dragana Josifova5,
  15. Annelise Nehammer5,
  16. Mina Ryten5,
  17. Debbie Spain1,3,
  18. Mark Pitts4,
  19. Jessica Bramham13,
  20. Philip Asherson1,
  21. Sarah Curran1,
  22. Evangelos Vassos1,
  23. Gerome Breen1,14,
  24. Frances Flinter5,
  25. Caroline Mackie Ogilvie9,
  26. David A Collier1,15,
  27. Stephen W Scherer6,7,16,
  28. Grainne M McAlonan3,4,14,
  29. Declan G Murphy3,4,14
  1. 1MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  2. 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy
  3. 3Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  4. 4Adult Autism Spectrum and ADHD Services, Behavioural and Developmental Psychiatry, Clinical Academic Group, King's Health Partners, London, UK
  5. 5Department of Clinical Genetics, Guy's and St Thomas’ NHS Foundation Trust, London, UK
  6. 6The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  7. 7Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  8. 8Individual Differences, Language and Cognition Lab, Department of Developmental and Educational Psychology, University of Seville, Seville, Spain
  9. 9Department of Cytogenetics, Guy's and St Thomas’ NHS Foundation Trust, London, UK
  10. 10Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  11. 11Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  12. 12Population Diagnostics, Inc., Melville, New York, USA
  13. 13UCD School of Psychology, University College Dublin, Dublin, Ireland
  14. 14National 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
  15. 15Discovery Neuroscience Research, Eli Lilly and Company Ltd, Erl Wood Manor, Windlesham, Surrey, UK
  16. 16Department of Molecular Genetics, McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Maria Tropeano, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK; maria.tropeano{at}kcl.ac.uk, tropeanomaria{at}gmail.com

Abstract

Background 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.

Methods 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).

Results 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).

Conclusions 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.

  • Neurodevelopment
  • Copy number variation
  • Dosage-sensitive gene
  • Enhancer
  • Female

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