J Med Genet 48:48-54 doi:10.1136/jmg.2010.079426
  • Original article

Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability

Open AccessEditor's Choice
  1. Anthony P Monaco1
  1. 1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  2. 2The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  3. 3Neural Development Unit, UCL Institute of Child Health, London, UK
  4. 4Citogenetica, Eugenio Medea Scientific Institute, Bosisio Parini, Italy
  5. 5Biologia Molecolare, Eugenio Medea Scientific Institute, Bosisio Parini, Italy
  6. 6The Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
  7. 7Department of Child Psychopathology, Eugenio Medea Scientific Institute, Bosisio Parini, Italy
  8. 8Department of Psychiatry, Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, California, USA
  9. 9Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA
  10. 10Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
  11. 11Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio, USA
  1. Correspondence to Professor Anthony P Monaco, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK; anthony.monaco{at}
  • Received 19 April 2010
  • Revised 11 August 2010
  • Accepted 16 August 2010
  • Published Online First 23 October 2010


Background Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD.

Methods In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos.

Results The deletion of chr16: 60 025 584–61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527–60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex.

Conclusion Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.


  • Funding Funding for this work comes from the Simons Foundation, the Nancy Lurie Marks Family Foundation, the Wellcome Trust (075491/Z/04), the NIH (MH086117), a Telethon Grant (GGP06208A/B), Autism Speaks, Autistica, Genome Canada/Ontario Genomics Institute, Canadian Institutes for Health Research, The Centre for Applied Genomics and the McLaughlin Centre. Tissue for the in situ work was provided by the MRC/Wellcome Trust Human Developmental Biology Resource.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Family 3099: Joint Ethics Committee (Newcastle & North Tyneside Health Authority/Universities of Newcastle upon Tyne/Northumbria). Family 09: The Ethics Committee at the ”E. Medea” Scientific Institute. The HDBR has tissue bank ethics approval from the National Research Ethics Service.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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