16p11.2 Copy Number Variations and Neurodevelopmental Disorders

Abstract

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.

Keywords: 16p11.2 deletion and duplication; autism spectrum disorders; clinical phenotypes; mouse models; prefrontal cortex.

Figure 1.. Common phenotypes in carriers of 16p11.2 CNVs.

Both 16p11.2 deletions and duplications predispose individuals to ASD, ID, epilepsy/seizures, and DF/CA with high penetrance, in addition to several other common phenotypes. Numbers inside parentheses indicate ranges of reported penetrance within cohorts of 16p11.2 CNV patients. Inset: Genes in the human 16p11.2 region. ASD: autism spectrum disorder; ID: intellectual disability; DF/CA: dysmorphic features/congenital anomalies.

Figure 2.. Summary of main preclinical findings from mouse models of 16p11.2 deletion and duplication.

Studies in 16p11.2 CNV transgenic mice have identified several core behavioral abnormalities, along with associated neurobiological disruptions. The deletion or duplication of genes within the 16p11.2 region drives transcriptional dysregulation of various downstream pathways. These transcriptional changes in turn lead to the altered developmental trajectories and synaptic changes across distributed brain regions. A range of behavioral phenotypes are reported in both 16p11.2 deletion and duplication models, likely driven by structural/functional neurological changes. Preclinical studies have identified several therapeutic approaches targeting selected disrupted systems. *KEY FIGURE

Figure 3.. Schematic showing molecular and cellular mechanisms of 16p11.2 genes and interacting partners in nucleus, soma and synapses.

Proteins encoded by genes in 16p11.2 region are labeled with yellow. At glutamatergic synapses, Prrt2 and Doc2a are involved in regulating presynaptic transmitter release. TaoK2 and Erk1 act on postsynaptic actin cytoskeleton via RhoA signaling, which contributes to the deficits of spine structure and synaptic excitation associated with 16p11.2 deletions. Kctd13 is an adaptor of the E3 ligase Cul3, controlling the degradation of RhoA and other protein substrates. The therapeutic agent CTEP acts on mGluR5 to modify glutamatergic responses. At GABAergic synapses, the therapeutic agent R-baclofen acts on presynaptic GABA_B receptors to regulate GABA release. Erk1 regulates the phosphorylation of GABA_A receptor channels. In the nucleus, 16p11.2 CNVs could induce the alterations of chromatin remodeling and gene transcription. The expression of Npas4, a key regulator of GABA synapses via BDNF, is downregulated in 16p11.2 duplication mice, which contributes to the deficits of synaptic inhibition.