Human Gene Module / Chromosome 17 / ACE

ACEangiotensin I converting enzyme

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
7 / 2
Aliases
ACE, ACE1,  CD143,  DCP,  DCP1,  ICH,  MVCD3
Associated Syndromes
-
Chromosome Band
17q23.3
Associated Disorders
-
Relevance to Autism

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene (p.Tyr818Cys) was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP. Functional analysis of the ASD-associated p.Tyr818Cys missense variant in Drosophila in Marcogliese et al., 2022 demonstrated a gain-of-function effect (increased lethality when overexpressed ubiquitously compared to reference protein).

Molecular Function

This gene encodes an enzyme that plays a key role in the renin-angiotensin system and is involved in catalyzing the conversion of angiotensin I into a physiologically active peptide angiotensin II, a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ACE (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study Firouzabadi N et al. (2016) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Marcogliese PC et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2810C>T p.Pro937Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.954C>T p.Asn318%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3490G>A p.Gly1164Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2453A>G p.Tyr818Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3649G>T p.Glu1217Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1030_1045del p.Glu344ArgfsTer107 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.92del p.Asp31AlafsTer114 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2328G>A;c.606G>A;c.1779G>A;c.666G>A p.(=) synonymous_variant - - - 27082637 Firouzabadi N et al. (2016)
c.2306-117_2306-116insAF118569 - intron_variant - - - 27082637 Firouzabadi N et al. (2016)
SFARI Gene score
2

Strong Candidate

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2016
icon
4

Increased from to 4

Description

Association between two polymorphisms of the ACE gene thought to regulate the level of enzyme activity (the insertion/deletion polymorphism and rs4343) and autism was observed in a case-control analysis of 120 Iranian ASD cases and 120 age and sex-matched controls of Caucasin origin (Firouzabadi et al., 2016). A de novo predicted damaging missense variant in the ACE gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), however this variant was also reported in dbSNP.

Krishnan Probability Score

Score 0.46436328687902

Ranking 9212/25841 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.
Original Source
ExAC Score

Score 4.6328287445365E-18

Ranking 17880/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.86440123128029

Ranking 4039/18665 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).
Original Source
Zhang D Score

Score -0.07644790784533

Ranking 11430/20870 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.
Original Source
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