Cognitive and Head Circumference Differences in 16p11.2 CNV Carriers with and without Autism.
Objectives: The aim of this study is to characterize cognitive dimensions and head circumference (HC) –a proxy for brain size – in carriers of a 16p11.2 copy number variant (CNV) with ASD and those without ASD.
Methods: A total of 265 probands carrying 16p11.2 rearrangements (174 deletion; 91 duplication) and 421 intrafamilial controls recruited from the 16p11.2 European Consortium, the Cardiff University Experiences of Children with Copy Number Variants Study and the Simons Variation in Individuals Project were included in the study. Measures included HC, ADI-R and IQ. We used linear mixed models to compare differences in phenotype between deletion and duplication carriers with and without ASD.
Results: Both the deletion and the duplication are associated with an IQ that is about 25 points lower than familial controls. ASD diagnosis in deletion carriers is associated with a 6.6-point increase in IQ mainly driven by nonverbal skills (p=0.018) and larger HC (+0.78 z-score, p=0.001) compared to deletion carriers without ASD. In contrast, duplication carriers with ASD show an additional decrease of 15 points in IQ (p= 0.002) compared to duplication carriers without ASD. Additional genetic factors underlying the ASD diagnosis in deletion carriers may be inherited since mothers have a significantly higher IQ (8 points; p=0.006) compared to mothers of carriers without ASD. The clinical profile of duplication carriers with ASD also differs significantly from that of deletion carriers with ASD. The former display more repetitive and stereotyped behaviors on the ADI-R (p=0.01).
Conclusions: The clinical differences between CNV carriers with and without ASD may inform on the nature of the additional factors present in the subgroup diagnosed with ASD. In addition, these results highlight the fact that deletion and duplication at the 16p11.2 locus are associated with two distinct underlying mechanisms predisposing to ASD.