Human Gene Module / Chromosome 7 / GIGYF1

GIGYF1GRB10 interacting GYF protein 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 14
Rare Variants / Common Variants
62 / 0
EAGLE Score
17.25
Strong Learn More
Aliases
GIGYF1, PP3360,  GYF1,  PERQ1
Associated Syndromes
Tourette syndrome
Chromosome Band
7q22.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

Two de novo likely gene-disruptive/protein-truncating variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). Additional de novo likely gene-disruptive/protein-truncating variants in GIGYF1 were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); six protein-truncating variants in this gene were also observed in case samples from the Danish iPSYCH study in Satterstrom et al., 2020. Furthermore, independent TADA analyses in Feliciano et al., 2019 and Satterstrom et al., 2020 identified GIGYF1 as an ASD candidate gene with a false discovery rate (FDR) 0.01. Analysis of whole-exome sequencing or whole-genome sequencing data from the SPARK cohort and the Simons Simplex Collection in Chen et al., 2022 identified a significant de novo enrichment (P<2.7E-12) and significant transmission disequilibrium (P<1E-05) of GIGYF1 heterozygous likely gene-disruptive (LGD) variants in these two cohorts; a recurrent LGD variant in GIGYF1 (c.332del;p.Leu111ArgfsTer234) that was detected in 23 ASD individuals from 20 families or singleton cases and shown experimentally to result in abnormal cellular localization in mouse primary cultured neurons also showed significant de novo enrichment (P=0.0004) and significant transmission disequilibrium (P=0.03). Additional mouse model studies in Chen et al., 2022 demonstrated Gigyf1 conditional knockout mice exhibited social impairments without significant cognitive impairments and a reduction of upper layer cortical neurons accompanied by decreased proliferation and increased differentiation of neural progenitor cells.

Molecular Function

The protein encoded by this gene may act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling and may increase IGF1 receptor phosphorylation under IGF1 stimulation as well as phosphorylation of IRS1 and SHC1 (by similarity).

SFARI Genomic Platforms
Reports related to GIGYF1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
4 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
5 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
9 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism Breuss MW , et al. (2019) Yes -
10 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
11 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
12 Support - Mahjani B et al. (2021) Yes -
13 Support - Woodbury-Smith M et al. (2022) Yes -
14 Recent Recommendation - Chen G et al. (2022) Yes DD, ID
Rare Variants   (62)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2653G>T p.Glu885Ter stop_gained Unknown - - 35917186 Chen G et al. (2022)
c.439C>T p.Arg147Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.175G>T p.Glu59Ter stop_gained Unknown - Unknown 35917186 Chen G et al. (2022)
c.595C>T p.Arg199Cys missense_variant De novo NA - 35917186 Chen G et al. (2022)
c.439C>T p.Arg147Ter stop_gained Unknown - Unknown 35917186 Chen G et al. (2022)
c.763C>T p.Arg255Ter stop_gained Unknown - Unknown 35917186 Chen G et al. (2022)
c.979C>T p.Gln327Ter stop_gained Unknown - Unknown 35917186 Chen G et al. (2022)
c.1731-1G>A - splice_site_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.2193+1G>A - splice_site_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.661C>T p.Arg221Ter stop_gained De novo NA - 31452935 Feliciano P et al. (2019)
c.2407C>T p.Arg803Ter stop_gained Unknown - Unknown 35917186 Chen G et al. (2022)
c.370C>T p.Arg124Ter stop_gained De novo NA Simplex 35917186 Chen G et al. (2022)
c.439C>T p.Arg147Ter stop_gained De novo NA Simplex 35917186 Chen G et al. (2022)
c.2761+2T>C - splice_site_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.1810C>T p.Gln604Ter stop_gained De novo NA Simplex 31873310 Breuss MW , et al. (2019)
c.949-2A>G - splice_site_variant Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.474G>A p.Trp158Ter stop_gained Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.772C>T p.Arg258Ter stop_gained Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.1291-1G>A - splice_site_variant Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.1970-1G>C - splice_site_variant Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.2193+1G>T - splice_site_variant Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.2869C>T p.Gln957Ter stop_gained Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.3034C>T p.His1012Tyr missense_variant De novo NA Simplex 31771860 Cappi C , et al. (2019)
c.2610C>G p.Tyr870Ter stop_gained De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1489G>T p.Glu497Ter stop_gained Familial Paternal Multiplex 35917186 Chen G et al. (2022)
c.3000G>A p.Glu1000%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.242C>T p.Pro81Leu missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2870A>G p.Gln957Arg missense_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.482+7C>G - splice_region_variant De novo NA Multiplex 31981491 Satterstrom FK et al. (2020)
c.707G>A p.Arg236His missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.331dup p.Leu111ProfsTer20 frameshift_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.992del p.Phe331SerfsTer14 frameshift_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.3034C>T p.His1012Tyr missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.332del p.Leu111ArgfsTer234 frameshift_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.1913C>A p.Ser638Ter stop_gained Unknown Not maternal Multiplex 35917186 Chen G et al. (2022)
c.3106T>G p.Ter1036GlyextTer72 stop_lost De novo NA Multiplex 32094338 Husson T , et al. (2020)
c.451dup p.Glu151GlyfsTer10 frameshift_variant Unknown - Multiplex 35917186 Chen G et al. (2022)
c.332del p.Leu111ArgfsTer234 frameshift_variant De novo NA Simplex 35917186 Chen G et al. (2022)
c.521del p.Gly174GlufsTer171 frameshift_variant De novo NA Simplex 35917186 Chen G et al. (2022)
c.2331dup p.Gln778AlafsTer43 frameshift_variant De novo NA Simplex 35917186 Chen G et al. (2022)
c.2498dup p.Gly834ArgfsTer35 frameshift_variant De novo NA Simplex 35917186 Chen G et al. (2022)
c.475del p.Asp159MetfsTer186 frameshift_variant Unknown - Multiplex 35917186 Chen G et al. (2022)
c.163A>G p.Lys55Glu missense_variant Unknown Not maternal Multiplex 30564305 Guo H , et al. (2018)
c.332del p.Leu111ArgfsTer234 frameshift_variant De novo NA Multiplex 35917186 Chen G et al. (2022)
c.2441del p.Leu814ArgfsTer44 frameshift_variant De novo NA Multiplex 35917186 Chen G et al. (2022)
c.1236_1239dup p.Gly414CysfsTer10 frameshift_variant Unknown - Unknown 35917186 Chen G et al. (2022)
c.944_945del p.Leu315GlnfsTer10 frameshift_variant Unknown - Multiplex 35917186 Chen G et al. (2022)
c.1172_1175del p.Lys391SerfsTer14 frameshift_variant Unknown - Multiplex 35917186 Chen G et al. (2022)
c.332del p.Leu111ArgfsTer234 frameshift_variant Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.332del p.Leu111ArgfsTer234 frameshift_variant Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.1947del p.His649GlnfsTer28 frameshift_variant Familial Paternal Simplex 35917186 Chen G et al. (2022)
c.3097del p.Asp1033MetfsTer14 frameshift_variant Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.2647del p.Glu883ArgfsTer7 frameshift_variant Unknown Not maternal Simplex 35917186 Chen G et al. (2022)
c.332del p.Leu111ArgfsTer234 frameshift_variant Familial Maternal Multiplex 35917186 Chen G et al. (2022)
c.2228dup p.Gln744AlafsTer77 frameshift_variant Familial Maternal Multiplex 35917186 Chen G et al. (2022)
c.1140_1156del p.Thr381ArgfsTer13 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1481_1485dup p.Ala496ArgfsTer17 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.332del p.Leu111ArgfsTer234 frameshift_variant Unknown Not maternal Simplex 35917186 Chen G et al. (2022)
c.2688_2689del p.Arg897AlafsTer39 frameshift_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.2453_2454insA p.Ser819ValfsTer2 frameshift_variant Familial Maternal Simplex 35917186 Chen G et al. (2022)
c.274_275del p.Leu92ValfsTer38 frameshift_variant Unknown Not maternal Multiplex 35917186 Chen G et al. (2022)
c.663_664insAGACG p.Asp222ArgfsTer125 frameshift_variant Unknown - Extended multiplex 35917186 Chen G et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

1

High Confidence

See all Category 1 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.

10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

4/1/2015
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the GIGYF1 gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Krishnan Probability Score

Score 0.44633276596467

Ranking 14840/25841 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 0.97870481168011

Ranking 2177/18225 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
Sanders TADA Score

Score 0.018633889054451

Ranking 33/18665 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).
Larsen Cumulative Evidence Score

Score 12

Ranking 158/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.36416429410477

Ranking 1858/20870 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.
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