16.5 CARVING CLINICAL HETEROGENEITY AT ITS JOINTS: THE POTENTIAL ROLE OF COPY NUMBER VARIATION IN UNDERSTANDING AUTISM SPECTRUM DISORDER

Abstract

Autism spectrum disorder (ASD) is characterized by marked clinical heterogeneity. Copy number variation (CNV), a type of structural genetic variation involving the deletion or duplication of a DNA segment, may help parse this heterogeneity by defining ASD subtypes. Several CNV-associated ASD syndromes have been described with characteristic phenotypes. This presentation will focus on 1 such syndrome, 16p11.2 CNV, and will include a discussion of recent unpublished work that we have conducted with this population. We will discuss what is known about the 16p11.2 CNV. We will then describe the results and implications of the recent work we conducted with a small (n = 19) pilot sample of 16p11.2 CNV carriers. 16p11.2 duplication and 16p11.2 deletion are both associated with ASD, but their clinical phenotypes otherwise diverge in notable ways. 16p11.2 duplication is associated with microcephaly, thinness, and a variable degree of intellectual impairment (from mild to severe). 16p11.2 deletion is associated with macrocephaly, obesity, and consistently severe intellectual impairment. Notably, 16p11.2 duplication, but not the deletion, is also associated with schizophrenia. In a small pilot study, we conducted in-depth interviews with 16p11.2 duplication and deletion carriers and assessed them for formal thought disorder. We found a suggestion of quantitative differences in thought process between the 2 groups. Given the small size of our pilot sample, our findings are not definitive. However, they represent a proof of concept that CNVs represent a way to identify subtle, detectable differences between people with ASD that would otherwise be obscured by the disorder’s overall heterogeneity and that may have clinical meaning.