Evaluating heterogeneity in ASD symptomatology, cognitive ability, and adaptive functioning among 16p11.2 CNV carriers

Abstract

Individuals with 16p11.2 copy number variant (CNV) show considerable phenotypic heterogeneity. Although autism spectrum disorder (ASD) is reported in approximately 20–23% of individuals with 16p11.2 CNVs, ASD‐associated symptoms are observed in those without a clinical ASD diagnosis. Previous work has shown that genetic variation and prenatal and perinatal birth complications influence ASD risk and symptom severity. This study examined the impact of genetic and environmental risk factors on phenotypic heterogeneity among 16p11.2 CNV carriers. Participants included individuals with a 16p11.2 deletion (N = 96) or duplication (N = 77) with exome sequencing from the Simons VIP study. The presence of prenatal factors, perinatal events, additional genetic events, and gender was studied. Regression analyses examined the contribution of each risk factor on ASD symptomatology, cognitive functioning, and adaptive abilities. For deletion carriers, perinatal and additional genetic events were associated with increased ASD symptomatology and decrements in cognitive and adaptive functioning. For duplication carriers, secondary genetic events were associated with greater cognitive impairments. Being female sex was a protective factor for both deletion and duplication carriers. Our findings suggest that ASD‐associated risk factors contribute to the variability in symptom presentation in individuals with 16p11.2 CNVs. Lay Summary There are a wide range of autism spectrum disorder (ASD) symptoms and abilities observed for individuals with genetic changes of the 16p11.2 region. Here, we found perinatal complications contributed to more severe ASD symptoms (deletion carriers) and additional genetic mutations contributed to decreased cognitive abilities (deletion and duplication carriers). A potential protective factor was also observed for females with 16p11.2 variations. Autism Res 2020, 13: 1300–1310. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

16p11.2 Copy Number Variations and Neurodevelopmental Disorders

“…Sex differences in 16p11.2 CNVs-Several neurodevelopmental disorders display a sex bias where males are at a higher risk [56]. In agreement with this, the ratio of males to females with either ASD or ID shows a male predominance in both 16p11.2 CNVs [57], suggesting that being female is a protective factor when predicting overall ASD severity in either 16p11.2 CNV [58]. However, another study found that sex was not a significant predictor of psychosis in 16p11.2 CNV carriers [44].…”

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion

“…The general lack of phenotypes in our and their coisogenic mouse models of 16p11.2 deletion could be interpreted as suggesting that developmental neuropsychiatric disorders seen at elevated rates among 16p11.2 deletion carriers are not primarily caused by this chromosomal deletion alone. This CNV might require other coexisting genetic variants, including second CNVs [ 44 ] and common genetic variation [ 21 , 45 ], and environmental insults, such as preterm and C-section birth [ 46 ] to be fully symptomatic. Alternatively, this CNV might manifest its impacts on subdimensions that are predominantly used for certain functions in a given species.…”

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

“…CNVs in 16p11.2 are among the most frequently identified pathogenic genetic changes in autism spectrum and other neurodevelopmental disorders [5,6]. They exemplify the variable expressivity and pleiotropy that tends to be the norm for high-risk genetic variants: deletions of this genomic interval are strongly associated with autism and intellectual disability [7], while duplications appear to increase risk more strongly towards psychotic disorders [8].…”