A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

Abstract

Objective: Certain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. Methods: This international study included 566 children (12.3 years (SD=4.2), 51% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (83 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 380 22q11.2 deletion carriers and 53 22q11.2 duplication carriers), as well as 2027 children (9.1 years (SD=4.9), 87% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted. Results: The four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (75% to 96% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to children with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of children with one of the 4CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits. Conclusion: Many CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.

Sub-diagnostic effects of genetic variants associated with autism

“…These differences increased when considering genes with high RR (Fig. 2b), indicating a gradient of severity of LoF variants in the general population as previously reported for large copy-number variants 20–22 .…”

Perspective on Beyond Statistical Significance: Finding Meaningful Effects

“…This implies that individual SNPs will rarely be good biomarkers or predictors of risk, but there is promise in combining them (see below). Even variations with large effect sizes, for example, copy number variants, show heterogeneity in the clinical symptoms they are associated with, presumably due to modification by the rest of the genome and the environment [19,20].…”

Patient brain organoids identify a link between the 16p11.2 copy number variant and the RBFOX1 gene

“…The CNVs spanning chromosome 16p11.2 have been associated with multiple neuropsychiatric and neurodevelopmental disorders 7 and are the focus of our current study. Some clinical diagnoses or phenotypes are common to both 16p11.2 hemideletion (1 copy loss) and hemiduplication (1 copy gain), such as autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy [7][8][9][10][11][12][13][14] . Other diagnoses or phenotypes are unique to the actual copy number and can be reciprocal between hemideletion and hemiduplication.…”