Human Gene Module / Chromosome 2 / GIGYF2

GIGYF2GRB10 interacting GYF protein 2

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
8 / 0
Aliases
GIGYF2, GYF2,  PARK11,  PERQ2,  PERQ3,  TNRC15
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
2q37.1
Associated Disorders
-
Relevance to Autism

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease.

Reports related to GIGYF2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
6 Support Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Rubinstein M , et al. (2016) Yes -
7 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2930G>A p.Arg977Gln missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1990C>T p.Gln664Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3527C>G p.Pro1176Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.958G>T p.Glu320Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3102_3113del p.Ser1035_His1038del inframe_deletion Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.2867G>A p.Arg956Gln missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.3651G>C p.Gln1217His missense_variant Familial - Extended multiplex 27956748 Rubinstein M , et al. (2016)
C>T p.Arg637Ter stop_gained De novo - - 28714951 Lim ET , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

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.

7/1/2017
2
icon
2

Score remained at 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A second de novo loss-of-function (LoF) variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A de novo postzygotic mosaic nonsense variant in GIGYF2 was identified in an ASD proband in Lim et al., 2017, bringing the total of de novo LoF variants in GIGYF2 to three.

1/1/2017
2
icon
2

Score remained at 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A fourth de novo LoF variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

10/1/2016
3
icon
2

Decreased from 3 to 2

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015). A fourth de novo LoF variant in GIGYF2 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

7/1/2015
icon
3

Increased from to 3

Description

Three de novo variants in the GIGYF2 gene (1 nonsense, 2 missense) have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=3.40 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.49228277258555

Ranking 4627/25841 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.
ExAC Score

Score 0.99999999997935

Ranking 53/18225 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
Iossifov Probability Score

Score 0.948

Ranking 84/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.25896648523786

Ranking 149/18665 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 0.34279934511242

Ranking 2107/20870 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 GIGYF2(1 CNVs)
2q37.1 20 Deletion-Duplication 37  /  99
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