Psychotic symptoms in 16p11.2 copy‐number variant carriers

Abstract

16p11.2 copy‐number variation (CNV) is implicated in neurodevelopmental disorders, with the duplication and deletion associated with autism spectrum disorder (ASD) and the duplication associated with schizophrenia (SCZ). The 16p11.2 CNV may therefore provide insight into the relationship between ASD and SCZ, distinct disorders that co‐occur at an elevated rate, and are difficult to distinguish from each other and from common co‐occurring diagnoses such as obsessive compulsive disorder (OCD), itself a potential risk factor for SCZ. As psychotic symptoms are core to SCZ but distinct from ASD, we sought to examine their predictors in a population (n = 546) of 16p11.2 CNV carriers and their noncarrier siblings recruited by the Simons Variation in Individuals Project. We hypothesized that psychotic symptoms would be most common in duplication carriers followed by deletion carriers and noncarriers, that an ASD diagnosis would predict psychotic symptoms among CNV carriers, and that OCD symptoms would predict psychotic symptoms among all participants. Using data collected across multiple measures, we identified 19 participants with psychotic symptoms. Logistic regression models adjusting for biological sex, age, and IQ found that 16p11.2 duplication and ASD diagnosis predicted psychotic symptom presence. Our findings suggest that the association between 16p11.2 duplication and psychotic symptoms is independent of ASD diagnosis and that ASD diagnosis and psychotic symptoms may be associated in 16p11.2 CNV carriers. Autism Res 2020, 13: 187–198. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Either deletion or duplication at chromosome 16p11.2 raises the risk of autism spectrum disorder, and duplication, but not deletion, has been reported in schizophrenia (SCZ). In a sample of 16p11.2 deletion and duplication carriers, we found that having the duplication or having an autism diagnosis may increase the risk of psychosis, a key feature of SCZ.

16p11.2 Copy Number Variations and Neurodevelopmental Disorders

“…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]. Thus, the association between 16p11.2 CNVs and ASD/ID, but not psychosis, may involve a sex bias.…”

“…Psychotic symptoms have also been reported in duplication (7/114 [6.1%]) and deletion (5/217 [2.3%]) carriers [34]. In one study, both 16p11.2 deletion and duplication carriers exhibited psychotic symptoms, though only the duplication was a significant predictor of psychotic symptoms [44]. Thus, 16p11.2 duplications predispose robustly to SZ and associated psychotic symptoms, with greater penetrance than 16p11.2 deletions.…”

Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

“…The absence of psychosis or schizophrenia among the studies reviewed here may reflect the relatively young mean age of the cohorts, who were yet to enter the age range usually associated with highest risk of emerging symptoms. Although many had an Autism Spectrum Disorder, the risks of psychosis are independent of autism in 16p11.2 duplication carriers [2].…”

“…Although often benign, a major advance in our understanding is that CNVs contribute significantly to risk for several neurodevelopmental and neuropsychiatric conditions, rare diseases and congenital malformation syndromes. However, variable penetrance and expression, syndromes, as well as pleiotropy, is reported [2]. Improved understanding of these risks has implications for more accurate and timely communication of the associated clinical risks.…”

“…Dysmorphic facial features and major malformations have also been observed, particularly in those 16p11.2 microduplications syndromal rare diseases [16]. 16p11.2 rearrangements may be overlooked by clinicians as they have variable penetrance and pleiotropic effects [2]. Their detection, however, may identify important genetic causes of neurodevelopmental and neuropsychiatric presentation that are useful in a clinical genetics context to inform genetic counselling and more broadly to inform clinical care for deletion carriers.…”