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Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size
  1. Marwan Shinawi1,2,
  2. Pengfei Liu1,
  3. Sung-Hae L Kang1,
  4. Joseph Shen3,
  5. John W Belmont1,2,
  6. Daryl A Scott1,2,
  7. Frank J Probst1,2,
  8. William J Craigen1,2,
  9. Brett H Graham1,2,
  10. Amber Pursley2,
  11. Gary Clark4,
  12. Jennifer Lee4,
  13. Monica Proud4,
  14. Amber Stocco4,
  15. Diana L Rodriguez4,
  16. Beth A Kozel5,
  17. Steven Sparagana6,
  18. Elizabeth R Roeder7,
  19. Susan G McGrew8,
  20. Thaddeus W Kurczynski9,
  21. Leslie J Allison10,
  22. Stephen Amato11,
  23. Sarah Savage11,
  24. Ankita Patel1,
  25. Pawel Stankiewicz1,12,
  26. Arthur L Beaudet1,2,
  27. Sau Wai Cheung1,
  28. James R Lupski1,2,13
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  2. 2Texas Children's Hospital, Houston, Texas, USA
  3. 3Children's Hospital Central California, Madera, California, USA
  4. 4Section of Neurology, Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
  5. 5Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
  6. 6Department of Neurology, Texas Scottish Rite Hospital for Children and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  7. 7Department of Pediatrics, Division of Genetics and Metabolic Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
  8. 8Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  9. 9Department of Pediatrics, Akron Children's Hospital, Akron, Ohio, USA
  10. 10Monarch Medical Clinic, Katy, Texas, USA
  11. 11Department of Medical Genetics, Eastern Maine Medical Center, Bangor, Maine, USA
  12. 12Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
  13. 13Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr Sau Wai Cheung, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, Texas 77030, USA; scheung{at}


Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.

Method We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.

Results The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.

Conclusions Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.

  • Developmental delay
  • autism
  • copy number variations
  • macrocephaly and microcephaly
  • epilepsy

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  • Competing interests Declaration: Some authors are based in the Department of Molecular and Human Genetics at Baylor College of Medicine (BCM), which offers extensive genetic laboratory testing, including use of arrays for genomic copy number analysis, and derives revenue from this activity. JRL is a consultant for Athena Diagnostics, 23 and Me, and Ion Torrent Systems.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the IRB-Baylor College of Medicine, Houston, Texas, USA.

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