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Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder
  1. Bridget A Fernandez1,3,
  2. Wendy Roberts5,
  3. Brian Chung6,
  4. Rosanna Weksberg6,
  5. Stephen Meyn6,
  6. Peter Szatmari7,
  7. Ann M Joseph-George8,10,
  8. Sara MacKay3,
  9. Kathy Whitten3,
  10. Barbara Noble3,
  11. Cathy Vardy2,4,
  12. Victoria Crosbie4,
  13. Sandra Luscombe4,
  14. Eva Tucker4,
  15. Lesley Turner1,3,
  16. Christian R Marshall8,
  17. Stephen W Scherer8,9
  1. 1Discipline of Genetics, Memorial University of Newfoundland, St John's, Newfoundland, Canada
  2. 2Discipline of Pediatrics Memorial University of Newfoundland, St John's, Newfoundland, Canada
  3. 3Provincial Medical Genetics Program, Eastern Health, St. John's, Newfoundland, Canada
  4. 4Child Health Program, Eastern Health, St. John's Newfoundland, Canada
  5. 5The Autism Research Unit, Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
  7. 7Offord Center for Child Studies, McMaster University, Hamilton, Ontario, Canada
  8. 8The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada
  9. 9Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  10. 10Department of Pediatric Laboratory Medicine, Cytogenetics Laboratory, Hospital for Sick Children, Toronto, Ontario, Canada
  1. Correspondence to Bridget Fernandez, Provincial Medical Genetics Program, Health Sciences Center, 300 Prince Philip Drive, St. John's Newfoundland, A1B 3V6, Canada; bfernandez{at}


Background Recurrent microdeletions and microduplications of ∼555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited.

Methods We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features.

Results Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (non-dysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence.

Conclusions The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with non-specific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity.

  • Autism spectrum disorder (ASD)
  • copy number variation (CNV)
  • microdeletion 16p11.2
  • microduplication 16p11.2
  • dysmorphology
  • clinical genetics
  • molecular genetics

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  • Funding Genome Canada/Ontario Genomics Institute, the Canadian Institutes of Health Research (CIHR), the McLaughlin Centre for Molecular Medicine, the Canadian Institute of Advanced Research, Autism Speaks, the McMaster Children's Hospital Foundation and the Hospital for Sick Children (SickKids) Foundation. CRM is supported by the SickKids Foundation and the National Alliance for Research on Schizophrenia and Depression (NARSAD). SWS holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto and Hospital for Sick Children.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Memorial University of Newfoundland; McMaster University; University of Toronto.

  • Patient consent Obtained.

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