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J Med Genet ; 47(5): 332-41, 2010 May.
Article in English | MEDLINE | ID: mdl-19914906

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.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 16/genetics , Developmental Disabilities/genetics , Adolescent , Attention Deficit Disorder with Hyperactivity/genetics , Autistic Disorder/genetics , Child , Child, Preschool , Chromosome Deletion , Comparative Genomic Hybridization , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , 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
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