Human Gene Module / Chromosome 15 / CHRNA7

CHRNA7cholinergic receptor, nicotinic, alpha 7

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 13
Rare Variants / Common Variants
26 / 0
Aliases
CHRNA7, CHRNA7-2,  NACHRA7
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
15q13.3
Associated Disorders
EPS, BPD, EP, ID, ASD, DD/NDD
Relevance to Autism

A rare deletion in the CHRNA7 gene has been identified with developmental delay and intellectual disability (Mikhail et al., 2011). In addition, a rare CHRNA7 duplication was found in two patients with autism and intellectual disability (Leblond et al., 2012).

Molecular Function

The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Reports related to CHRNA7 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Shinawi M , et al. (2009) No -
2 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
3 Primary Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental... Mikhail FM , et al. (2011) No ID
4 Support Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. Leblond CS , et al. (2012) Yes ID
5 Support Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype. Hoppman-Chaney N , et al. (2012) Yes -
6 Support Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders. Bartnik M , et al. (2012) No ASD, DD, ID
7 Support Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. Winiowiecka-Kowalnik B , et al. (2012) Yes DD/ID
8 Support Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci. Chilian B , et al. (2013) No -
9 Recent Recommendation CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree. Soler-Alfonso C , et al. (2014) Yes BPD, Epilepsy
10 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families. Egger G , et al. (2014) Yes -
11 Support Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility. Bacchelli E , et al. (2015) Yes -
12 Support 15q13.3 duplication in two patients with childhood-onset schizophrenia. Zhou D , et al. (2016) No -
13 Recent Recommendation Functional Consequences of CHRNA7 Copy-Number Alterations in Induced Pluripotent Stem Cells and Neural Progenitor Cells. Gillentine MA , et al. (2017) No -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 22031302 Mikhail FM , et al. (2011)
C>T - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
G>A - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
- - copy_number_gain Familial Maternal - 22825934 Bartnik M , et al. (2012)
- - copy_number_gain Familial Paternal - 23350639 Chilian B , et al. (2013)
- - copy_number_gain Familial Paternal - 25655306 Bacchelli E , et al. (2015)
c.27C>T - 5_prime_UTR_variant Unknown - - 25655306 Bacchelli E , et al. (2015)
- - copy_number_loss De novo - Unknown 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_loss Unknown - Unknown 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_gain Familial Paternal Multiplex 26968334 Zhou D , et al. (2016)
c.1-79G>A - 2KB_upstream_variant Unknown - - 25655306 Bacchelli E , et al. (2015)
- - copy_number_loss Familial Paternal Multiplex 24643514 Egger G , et al. (2014)
c.1-129A>G - 2KB_upstream_variant Unknown - - 25655306 Bacchelli E , et al. (2015)
- - copy_number_gain Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
- - copy_number_gain Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
G>A p.Gly200Arg missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1-70_1-69delG - 2KB_upstream_variant Unknown - - 25655306 Bacchelli E , et al. (2015)
- - copy_number_gain Familial Paternal Multi-generational 26968334 Zhou D , et al. (2016)
c.1466G>A p.Glu452Lys missense_variant Familial Maternal - 25655306 Bacchelli E , et al. (2015)
- - copy_number_gain Familial Maternal Multiplex 23032108 Winiowiecka-Kowalnik B , et al. (2012)
- - copy_number_loss Familial Paternal Multi-generational 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_loss Familial Paternal (unconfirmed) Extended 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_loss Familial Maternal Possible multi-generational 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_loss Familial Paternal Possible multi-generational 22775350 Hoppman-Chaney N , et al. (2012)
- - copy_number_gain Familial Maternal and paternal Multi-generational 24424125 Soler-Alfonso C , et al. (2014)
c.[1-129A>G];[27C>T] - 2KB_upstream_variant, 5_prime_UTR_variant Familial Maternal and paternal - 25655306 Bacchelli E , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Increased from 3 to 4.1 + acc1

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018
3
icon
4.1 + acc1

Increased from 3 to 4.1 + acc1

Description

3

10/1/2017
3
icon
3

Increased from 3 to 3

Description

An association between autism and gene dosage has been demonstrated at a 1.6 Mb region of 15q13.3 including CHRNA7 (PMID 18805830). Smaller deletions encompassing only two genes (OTUD7A and CHRNA7) were later identified in ten individuals from four families with intellectual disability and seizures (PMID 19898479). Significant reduction was shown in CHRNA7 in the frontal cortex from Rett syndrome and autistic patients compared with controls (PMID 21840925). This score was arrived at via category 4.1 + altered expression or function in ASD cases vs. controls in any tissues.

4/1/2016
3
icon
3

Increased from 3 to 3

Description

An association between autism and gene dosage has been demonstrated at a 1.6 Mb region of 15q13.3 including CHRNA7 (PMID 18805830). Smaller deletions encompassing only two genes (OTUD7A and CHRNA7) were later identified in ten individuals from four families with intellectual disability and seizures (PMID 19898479). Significant reduction was shown in CHRNA7 in the frontal cortex from Rett syndrome and autistic patients compared with controls (PMID 21840925). This score was arrived at via category 4.1 + altered expression or function in ASD cases vs. controls in any tissues.

1/1/2015
3
icon
3

Increased from 3 to 3

Description

An association between autism and gene dosage has been demonstrated at a 1.6 Mb region of 15q13.3 including CHRNA7 (PMID 18805830). Smaller deletions encompassing only two genes (OTUD7A and CHRNA7) were later identified in ten individuals from four families with intellectual disability and seizures (PMID 19898479). Significant reduction was shown in CHRNA7 in the frontal cortex from Rett syndrome and autistic patients compared with controls (PMID 21840925). This score was arrived at via category 4.1 + altered expression or function in ASD cases vs. controls in any tissues.

7/1/2014
No data
icon
3

Increased from No data to 3

Description

An association between autism and gene dosage has been demonstrated at a 1.6 Mb region of 15q13.3 including CHRNA7 (PMID 18805830). Smaller deletions encompassing only two genes (OTUD7A and CHRNA7) were later identified in ten individuals from four families with intellectual disability and seizures (PMID 19898479). Significant reduction was shown in CHRNA7 in the frontal cortex from Rett syndrome and autistic patients compared with controls (PMID 21840925). This score was arrived at via category 4.1 + altered expression or function in ASD cases vs. controls in any tissues.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

An association between autism and gene dosage has been demonstrated at a 1.6 Mb region of 15q13.3 including CHRNA7 (PMID 18805830). Smaller deletions encompassing only two genes (OTUD7A and CHRNA7) were later identified in ten individuals from four families with intellectual disability and seizures (PMID 19898479). Significant reduction was shown in CHRNA7 in the frontal cortex from Rett syndrome and autistic patients compared with controls (PMID 21840925). This score was arrived at via category 4.1 + altered expression or function in ASD cases vs. controls in any tissues.

Krishnan Probability Score

Score 0.52280045046085

Ranking 1657/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Sanders TADA Score

Score 0.94288041024445

Ranking 15474/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.20475805153974

Ranking 4196/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with CHRNA7(1 CNVs)
15q13.3 66 Deletion-Duplication 102  /  417
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Adcy6 adenylate cyclase 6 Rat Protein Binding 25289 F1LSD1
ATXN1 ataxin 1 Human Protein Binding 6310 P54253
Gnaq guanine nucleotide binding protein, alpha q polypeptide Mouse Protein Binding 14682 P21279
Gnb3 guanine nucleotide binding protein (G protein), beta 3 Mouse Protein Binding 14695 Q61011
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