Trends in Neurosciences
Volume 43, Issue 11, November 2020, Pages 886-901
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Review
16p11.2 Copy Number Variations and Neurodevelopmental Disorders

https://doi.org/10.1016/j.tins.2020.09.001Get rights and content

Highlights

  • 16p11.2 deletions or duplications predispose individuals to neurodevelopmental diseases, including autism spectrum disorder, intellectual disability, epilepsy/seizures, dysmorphic features, congenital anomalies, macrocephaly, and microcephaly.

  • 16p11.2 CNV mouse models recapitulate many of the human behavioral phenotypes, with distinct representation of social and cognitive deficits.

  • Various forms of synaptic dysfunction are observed across distributed brain areas in 16p11.2 CNV mouse models.

  • Broad transcriptional dysregulation is found in 16p11.2 CNV mouse models and human carriers, extending far beyond genes within the 16p11.2 region.

  • Several 16p11.2 genes, including Mapk3, Kctd13, Taok2, are highly involved in abnormal cortical development in 16p11.2 CNVs.

  • Possible therapeutic intervention strategies include the restoration of excitation–inhibition balance and synaptic plasticity by targeting glutamate and GABA systems.

Copy number variations (CNVs) of the human 16p11.2 genetic locus are associated with a range of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and epilepsy. In this review, we delineate genetic information and diverse phenotypes in individuals with 16p11.2 CNVs, and synthesize preclinical findings from transgenic mouse models of 16p11.2 CNVs. Mice with 16p11.2 deletions or duplications recapitulate many core behavioral phenotypes, including social and cognitive deficits, and exhibit altered synaptic function across various brain areas. Mechanisms of transcriptional dysregulation and cortical maldevelopment are reviewed, along with potential therapeutic intervention strategies.

Section snippets

The Link between 16p11.2 Copy Number Variations and Neurodevelopmental Disorders

Genetic factors comprise a large proportion of the risk for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), schizophrenia (SZ), and intellectual disability (ID) [1]. Copy number variations (CNVs, i.e., deletion or duplication) of various susceptible genetic loci predispose individuals to these NDDs and other developmental abnormalities [2,3]. The human 16p11.2 gene locus (chromosome 16, position 11.2) is an approximately 500–600-kb region containing 27–29 genes [4.,

Prevalence of 16p11.2 CNVs

Genetics Home Reference estimates that 16p11.2 deletions and duplications each affect about three in every 10 000 individuals.i,ii A predictive algorithm estimated 16p11.2 deletions to affect one in every 3021 live births, and duplications one in every 4216 [28]. These estimates are supported by large genetic screenings [20,24,29]. 16p11.2 deletions have been reported at rates of 0.028–0.043% in the general population, while duplications have been reported between 0.035% and 0.053% (Table 1).

Insights from Preclinical Studies in 16p11.2 CNV Mouse Models

Here we describe behavioral phenotypes in 16p11.2 CNV mouse models, and synthesize the major biological takeaways and implications (Figure 2, Figure 3). Three lines of 16p11.2 CNV mice have been generated: 16p11.2 mice (Mills) carrying deletion (16p11.2+/–) or duplication (16p11.2dp/+) of the 7F4 region (Slx1b-Sept1) syntenic to human 16p11.2 [5]; 16p11.2 mice (Dolmetsch) with deletion of the Coro1a-Spn interval [4]; 16p11.2 mice (Herault) with deletion/duplication of the Sult1a1-Spn genetic

Concluding Remarks and Future Perspectives

Clinical and preclinical investigations illustrate the diverse neurobiological impact of 16p11.2 CNVs. A number of highly penetrant developmental phenotypes are linked to both 16p11.2 deletions and duplications (Figure 1). Given the effects of 16p11.2 CNVs on 27–29 genes, these mutations have the capacity to cause broad and severe downstream biochemical insults across various brain areas. The array of cellular changes in 16p11.2 models, including transcriptional and synaptic dysregulation,

Acknowledgments

This work was supported by grants from Nancy Lurie Marks Family Foundation and National Institutes of Health (MH112237) to Z.Y.

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