Elsevier

Biochemical Pharmacology

Volume 97, Issue 4, 15 October 2015, Pages 352-362
Biochemical Pharmacology

Review
The human clinical phenotypes of altered CHRNA7 copy number

https://doi.org/10.1016/j.bcp.2015.06.012Get rights and content

Abstract

Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the α7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed.

Introduction

Copy number variation of chromosome 15q13 has been implicated in several neuropsychiatric diseases. The proximal part of chromosome 15 is one of the least stable regions in the genome, largely due to the presence of six low copy repeat (LCR) elements that cluster into six breakpoints (BP1–BP6), mediating non-allelic homologous recombination (NAHR), leading to chromosomal microdeletions and -duplications. Between BP1 and BP3, deletions are known to result in Prader–Willi syndrome when on the paternal chromosome and Angelman syndrome when on the maternal chromosome. Duplications of the same segment have been associated with autism, learning disabilities, and seizures. Telomeric to the Prader–Willi/Angelman syndrome region, at 15q13.3, CNVs have been observed in wide range of neuropsychiatric phenotypes, including cognitive deficits, schizophrenia, epilepsy, mood disorders, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) [1].

The CNVs at 15q13.3 manifest incomplete penetrance, with deletions leading to neuropsychiatric phenotypes in approximately 80% of cases [2] and duplications having much lower penetrance [1]. The most common deletions span from BP4 to BP5, a region containing six genes: FAN1, MTMR10, TRPM1, KLF13, OTUD7A and CHRNA7 and one microRNA: hsa-miR-211. Of these genes, CHRNA7 has been suggested as playing a major role in the neuropsychiatric phenotypes observed in patients.

In this review, we will discuss the entire spectrum of 15q13 CNVs, including homozygous deletions, heterozygous deletions, heterozygous duplications, and triplications, as well as their associated phenotypes. Cases were selected from the literature based on the report of phenotypic data beyond that used for ascertainment. We summarize a total of 363 patients from 54 publications, assuming that patients were not reported repeatedly in multiple publications. We propose that CHRNA7 is a dosage-sensitive gene, with more severe phenotypes caused by loss of copy number, and relatively milder effects by gain in copy number.

Section snippets

CHRNA7 as a candidate gene

CHRNA7 encodes for the α7 subunit of nicotinic acetylcholine receptors (nAChRs). Nicotinic acetylcholine receptors represent a family of ligand-gated ion channels and are members of the cys-loop receptor superfamily (reviewed by Schaaf, 2014) [3]. These ion channels have high expression in the brain, with highest expression of CHRNA7 in the hippocampus. Receptors comprised of α7 subunits are typically homopentameric, although they have also been shown to interact with β2 subunits [4] and

15q13.3 as a hotspot for genomic rearrangements

Chromosome 15q13 contains LCR elements clustering into BP1 to BP6. As a result, 15q13 is highly susceptible to NAHR, which likely results in many of the CNVs observed in the region. Distal to the Prader–Willi/Angelman syndrome region at BP1 to BP3, various recurrent microdeletions and microduplications occur between BP3 and BP5 (Fig. 1). The largest of these rearrangements are mediated by BP3 and BP5, spanning ∼3.4 Mb to ∼3.9 Mb. While BP3–BP4 deletions are known to occur, they will not be

15q13.3 microdeletion syndrome

15q13.3 deletion syndrome (OMIM 612001) is caused by heterozygous deletions at 15q13.3, ranging in size from ∼350 kb to 3.9 Mb. The estimated frequency of 15q13.3 microdeletions in patients with ID is approximately 0.29%. This is comparable to the prevalence of Angelman syndrome (0.34%), Prader–Willi syndrome (0.22%) and Williams syndrome (0.31%) in patients with ID [15]. Additionally, deletions of CHRNA7 are found in ∼1% of individuals with IGE and have been found to be overrepresented in

Shared clinical phenotypes of patients with CHRNA7 CNVs

Patients with both CHRNA7 gains and losses have been found to manifest a similar range of neuropsychiatric phenotypes, suggesting that the human brain is sensitive to CHRNA7 dosage. Dosage sensitivity is often observed in synaptopathies, such as the neuropsychiatric phenotypes associated with both deletions and duplications of SHANK3 and MECP2 [63]. We have assessed the common phenotypes between the heterozygous deletions and duplications of CHRNA7 (Table 1). Overall, almost half (n = 160, 44.1%)

Potential explanations for incomplete penetrance and variable expressivity of 15q13.3 CNVs

Individuals with CNVs involving CHRNA7 manifest a range of phenotypes that is primarily neurobehavioral or neuropsychiatric, but the penetrance of these phenotypes is incomplete, and among those who are clinically affected, there is great variability in severity and expressivity. One would assume that altered dosage of CHRNA7 leads to changes in α7 protein abundance, subsequently changing calcium signaling in respective domains of the central nervous system. But the genetic and/or environmental

Clinical implications

Deletions of chromosome 15q13.3 represent a rare, but well-defined cause of neurocognitive deficits and psychiatric disease. The incomplete penetrance and variable expressivity of the associated phenotypes, even within the same family, represent a significant challenge in counseling affected families, both in a pre- and postnatal setting. Even more challenging appears to be the situation for individuals affected with copy number gains involving CHRNA7, because of their uncertain pathogenicity.

Conclusions

Variations in copy number of CHRNA7 have been found to be associated with a wide range of phenotypes, including cognitive deficits, language and speech impairments, ASD, and mood disorders. The CHRNA7 gene appears to be critically dosage-sensitive with most profound phenotypes in individuals with zero copies of the gene, moderately severe neuropsychiatric disease in those with heterozygous deletions, and incompletely penetrant disease in individuals with more than two copies of the gene. The

Acknowledgements

This work was generously supported by the Doris Duke Charitable Foundation Grant #2011034, by the Joan and Stanford Alexander Family and by the NIGMS training grant T32 GM08307 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. We thank Jiani Yin, Janson White, and Evan Jones for their

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