Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

J Med Genet. 2010 May;47(5):332-41. doi: 10.1136/jmg.2009.073015. Epub 2009 Nov 12.

Abstract

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 ( 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Autistic Disorder / genetics
  • Child
  • Child, Preschool
  • Chromosome Aberrations*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 16 / genetics*
  • Comparative Genomic Hybridization
  • Craniofacial Abnormalities / genetics
  • Craniofacial Abnormalities / pathology
  • Developmental Disabilities / genetics*
  • Epilepsy / genetics
  • Female
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Language Development Disorders / genetics
  • Male
  • Microcephaly / genetics
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Segmental Duplications, Genomic
  • Young Adult