BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.