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. 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 (~40%), behavioural problems (~40%), congenital anomalies (~30%), and autism (~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.

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

“…A reverse correlation was described in patients with recurrent CNVs in 16p11.2. 51 The macro-and microcephaly observed in patients with CDKL5 duplications and deficiency, respectively, corroborate a diametric model of autism spectrum and psychotic spectrum behavioral phenotypes in genomic sister disorders. 52 Unlike CDKL5 deficiency, none of the presented patients with duplication had epilepsy and patients 3 and 7 had normal EEGs.…”

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

“…[1][2][3][4] Although some of the relatively larger CNVs have been associated with recognizable genomic disorders, [5][6][7][8][9][10][11][12] others have been implicated in causation of clinically overlapping neuro-developmental phenotypes, including autism spectrum disorders (ASDs), developmental delay (DD), and intellectual disability (ID). [13][14][15][16][17][18][19] More recently, smaller deletions or intragenic deletions disrupting a single gene have been associated with neurodevelopmental phenotypes.…”

Multiple roles of Ulk4 in neurogenesis and brain function

“…A good example of this is that reciprocal deletions and duplications of »600kb region at 16p11.2 are strongly associated with behavioral disorders, cognitive deficits and brain volume. 16p11.2 deletions are associated with speech/language and motor deficits, intellectual impairment, restrictive and repetitive behavior and macrocephaly, 28,29 whereas duplications are associated with ADHD, schizophrenia and microcephaly. 28,30 Decreased neurogenesis in the Ulk4 mutants has provided a cellular mechanism for its association with neurodevelopmental disorders.…”