title: Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.
abstract: BACKGROUND
  Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.
  
  
  METHODS
  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 ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, Texas 77030, USA; scheung@bcm.tmc.edu.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.forename: Joseph
authors.initials: J
authors.lastname: Shen
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.forename: Frank J
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authors.lastname: Probst
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.forename: Amber
authors.initials: A
authors.lastname: Pursley
authors.forename: Gary
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authors.lastname: Clark
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Monica
authors.initials: M
authors.lastname: Proud
authors.forename: Amber
authors.initials: A
authors.lastname: Stocco
authors.forename: Diana L
authors.initials: DL
authors.lastname: Rodriguez
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authors.lastname: Kozel
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authors.lastname: Sparagana
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Roeder
authors.forename: Susan G
authors.initials: SG
authors.lastname: McGrew
authors.forename: Thaddeus W
authors.initials: TW
authors.lastname: Kurczynski
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Allison
authors.forename: Stephen
authors.initials: S
authors.lastname: Amato
authors.forename: Sarah
authors.initials: S
authors.lastname: Savage
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D056916:Segmental Duplications, Genomic; D055815:Young Adult