Trends in Neurosciences
Review16p11.2 Copy Number Variations and Neurodevelopmental Disorders
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.
References (103)
The genetics of neurodevelopmental disease
Curr. Opin. Neurobiol.
(2011)Copy number variations in neurodevelopmental disorders
Prog. Neurobiol.
(2012)Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome
Cell Rep.
(2014)Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion
Transl. Psychiatry
(2018)The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population
Biol. Psychiatry
(2015)Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems
Genet. Med.
(2011)Extending the phenotype of current rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals
Eur. J. Med. Genet.
(2009)Psychiatric disorders in children with 16p11.2 deletion and duplication
Transl. Psychiatry
(2019)The number of genomic copies at the 16p11.2 locus modulates language, verbal memory, and inhibition
Biol. Psychiatry
(2016)Estimates of penetrance for recurrent pathogenic copy-number variations
Genet. Med.
(2013)
Structural variation of chromosomes in autism spectrum disorder
Am. J. Hum. Genet.
Study of the association between schizophrenia and microduplication at the 16p11.2 locus in the Han Chinese population
Psychiatry Res.
Rare and common variants at 16p11.2 are associated with schizophrenia
Schizophr. Res.
Quantifying the effects of 16p11.2 copy number variants on brain structure: a multisite genetic-first study
Biol. Psychiatry
Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 copy number variations
Neuroimage
In tribute to Bob Blanchard: Divergent behavioral phenotypes of 16p11.2 deletion mice reared in same-genotype versus mixed-genotype cages
Physiol. Behav.
16p11 Duplication disrupts hippocampal-orbitofrontal-amygdala connectivity, revealing a neural circuit endophenotype for schizophrenia
Cell Rep.
Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models
Neuron
Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families
Am. J. Hum. Genet.
Cellular phenotypes in human iPSC-derived neurons from a genetic model of autism spectrum disorder
Cell Rep.
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Am. J. Hum. Genet.
CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance through the promotion of Cap-dependent translation
Neuron
Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases
Neuron
TAOK2 kinase mediates PSD95 stability and dendritic spine maturation through Septin7 phosphorylation
Neuron
Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
Cell
Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice
Neuron
Global variation in copy number in the human genome
Nature
Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism
PNAS
KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant
Nature
16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2
Eur. J. Hum. Genet.
Microduplications of 16p11.2 are associated with schizophrenia
Nat. Genet.
Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities
JAMA Psychiatry
Recurrent 16p11.2 microdeletions in autism
Hum. Mol. Genet.
A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
J. Med. Genet.
Association between microdeletion and microduplication at 16p11.2 and autism
N. Engl. J. Med.
The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity
Mol. Psychiatry
Cognitive and behavioral characterization of 16p11.2 deletion syndrome
J. Dev. Behav. Pediatr.
Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications
J. Neurodev. Disord.
Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size
J. Med. Genet.
Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder
J. Med. Genet.
Autism spectrum disorder, developmental and psychiatric features in 16p11.2 duplication
J. Autism Dev. Disord.
A new highly penetrant form of obesity due to deletions on chromosome 16p11.2
Nature
Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2
Nat. Genet.
Opposing brain differences in 16p11.2 deletion and duplication carriers
J. Neurosci.
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Nature
Common variant at 16p11.2 conferring risk of psychosis
Mol. Psychiatry
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia
Mol. Psychiatry
An estimation of the prevalence of genomic disorders using chromosomal microarray data
J. Hum. Genet.
Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank
J. Med. Genet.
Longitudinal report of child with de novo 16p11.2 triplication
Clin. Case Rep.
Cited by (70)
Fatal cardiac dysfunction in a child with Williams syndrome
2024, Legal MedicineDevelopmental Disruptions of the Dorsal Striatum in Autism Spectrum Disorder
2024, Biological PsychiatryAssortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants
2023, American Journal of Human GeneticsMechanisms of copy number variants in neuropsychiatric disorders: From genes to therapeutics
2023, Current Opinion in Neurobiology