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

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.