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Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioral problems, dysmorphism, epilepsy, and abnormal head size
  1. Marwan Shinawi1,*,
  2. Pengfei Liu2,
  3. Sung-Hae L Kang2,
  4. Joseph Shen3,
  5. John W Belmont2,
  6. Daryl A Scott2,
  7. Frank J Probst2,
  8. William J. Craigen2,
  9. Brett Graham2,
  10. Amber Pursley2,
  11. Gary Clark4,
  12. Jennifer Lee4,
  13. Monica Proud4,
  14. Amber Stocco4,
  15. Diana Rodriguez4,
  16. Beth Kozel1,
  17. Steven Sparagana5,
  18. Elizabeth Roeder6,
  19. Susan McGrew7,
  20. Thaddeus Kurczynski8,
  21. Leslie Allison9,
  22. Stephen Amato10,
  23. Sarah Savage10,
  24. Ankita Patel2,
  25. Pawel Stankiewicz2,
  26. Arthur Beaudet2,
  27. Sau Wai Cheung2,
  28. James R. Lupski2
  1. 1 Washington University School of Medicine, United States;
  2. 2 Baylor College of Medicine, United States;
  3. 3 Children's Hospital Central California, United States;
  4. 4 Texas Children’s Hospital, United States;
  5. 5 Texas Scottish Rite Hospital for Children, United States;
  6. 6 University of Texas Health Science Center at San Antonio, United States;
  7. 7 Monroe Carell Jr. Children’s Hospital at Vanderbilt, United States;
  8. 8 Akron Children’s Hospital, United States;
  9. 9 Monarch Medical Clinic, United States;
  10. 10 Eastern Maine Medical Center, United States
  1. Correspondence to: Marwan Shinawi, Molecular Human Genetics, Washington University School of Medicine, One Children's Place, Northwest Tower, 9132, Campus Box 8116, St. Louis, 63105, United States; shinawi_m{at}kids.wustl.edu

Abstract

Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. We identified 27 deletions and 18 duplications of 16p11.2 in 0.6% of all samples submitted for clinical array-CGH analysis. The most common clinical manifestations in 17 deletion and ten duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (~40%), behavioral problems (~40%), congenital anomalies (~30%), and autism (~20%). The phenotypes among duplication patients included motor delay (6/10), behavioral problems (especially 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 six of the ten patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioral phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but two of the ten deletion cases in which parental studies were available. Additionally, two de novo cases were apparently mosaic for the deletion in the analyzed blood sample. Three de novo and two inherited cases were observed in the 5 of 10 duplication patients where data were available. 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 behavioral phenotypes in genomic sister disorders.

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