Intellectual disability
Gene: GIGYF1

GIGYF1 (GRB10 interacting GYF protein 1)
EnsemblGeneIds (GRCh38): ENSG00000146830
EnsemblGeneIds (GRCh37): ENSG00000146830
OMIM: 612064, Gene2Phenotype
GIGYF1 is in 2 panels

4 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

Comment on list classification: GIGYF1 shows statistically robust de novo enrichment for a complex neurodevelopmental disorder across three large cohorts of autism spectrum disorder patients (PMID:33057194, PMID:35917192, PMID:36924980), with supporting functional data in cell and animal models. However, only 25 individuals across the literature have detailed clinical phenotyping, of whom 11 had confirmed ID (no severity reported).

Although ClinGen rated it 'Definitive' for complex neurodevelopmental disorder, ClinGen's own review flags unresolved penetrance given recurrence of variants in unaffected parents/population controls. Gene2Phenotype recently downgraded this gene from 'moderate' to 'limited' confidence on the DD panel, and OMIM has no phenotype association as of August 2026.

Hence, this gene is rated amber based on all these evidences. The 'watchlist' tag has been added as recommendation for re-review as additional deeply phenotyped ID/GDD cases are published.
Created: 16 Aug 2026, 9:43 p.m. | Last Modified: 19 Aug 2026, 10:37 a.m.

Panel Version: 11.23

PMID:33057194 (2020) - This gene has been identified with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).

PMID:35917186 (2022) - 60 individuals carrying 35 distinct GIGYF1 likely gene-disruptive (LGD) variants, identified from SPARK/SSC autism cohorts (20,452 trios + 12,227 singletons) plus 7 additional GeneMatcher-ascertained probands. This cohort was ascertained specifically through ASD registries, so detailed non-ASD clinical/developmental phenotyping (including formal ID assessment) was not systematically reported for most of the 60 individuals. However, detailed clinical information was available for 11 patients, of which 9 patients had ASD, 10 had speech-language issues, 3 had motor delays, and 6 had ID. Severity of ID has not been provided for any of these patients.

PMID:36924980 (2023) - 26 de novo variants identified across a combined 44,665 NDD trios (ASD-primary and DD-primary cohorts). Of these, detailed clinical information was obtained for only 14 probands, of which 12 had ASD, 5 had DD, 5 had ID, 3 had motor delay and 8 had speech delay. Severity of ID has not been provided for any of these patients.

The pLI = 0 in gnomAD v4.1.1 for GIGYF indicating lack of constraint against LOF.

This gene has not yet been associated with any relevant phenotype in OMIM (last accessed 16 August 2026), but associated with GIGYF1-related developmental disorder with 'limited' rating on the DD panel of Gene2Phenotype. This gene was previously rated 'moderate/ on the DD panel in G2P and has been demoted in the last year.

This gene has been associated with 'Definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Intellectual Disability and Autism GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009351) However, ClinGen review noted that individuals with similar variants have also been observed in the general population or in reportedly unaffected parents of affected individuals, and deep phenotyping of parents in these studies is often unavailable. In addition, the extent of reduced penetrance and variable expressivity is currently unknown (PMID:35917186).
Created: 16 Aug 2026, 9:35 p.m. | Last Modified: 19 Aug 2026, 10:23 a.m.

Panel Version: 11.23

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
autism spectrum disorder, MONDO:0005258; neurodevelopmental disorder, MONDO:0700092

Publications

Created: 16 Aug 2026, 9:35 p.m.
Last Modified: 19 Aug 2026, 10:37 a.m.
Panel version: 11.20

Jana Jezkova (All Wales Medical Genomics Service)

I don't know

Non-specific phenotype. Large number of LoF variants in GnomAD and no LoF constraint. GIGYF1 was reported as the second-most mutated among known ASD high-confidence risk genes. (PMID:35917186). Tier 1, high-confidence developmental brain disorder gene in NDD GeneHub. GIGYF1 regulates recycling of IGF-1R to the cell surface; knockout reduced surface IGF-1R and disrupted IGF-1R/ERK signaling, providing a plausible NDD mechanism (PMID:36189799). Zebrafish and mouse LoF models recapitulated neurodevelopmental phenotypes (PMID:36924980).

PMID: 35917186 Number of Families: 55 Affected Individuals: 60
PMID: 36924980 Number of Families: 7 Affected Individuals: 7
Created: 25 Jun 2026, 2:07 p.m. | Last Modified: 25 Jun 2026, 2:07 p.m.

Panel Version: 10.30

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ASD; NDD

Publications

Created: 25 Jun 2026, 2:07 p.m.
Last Modified: 25 Jun 2026, 2:07 p.m.
Panel version: 10.30

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Created: 4 Dec 2020, 2:17 p.m. | Last Modified: 4 Dec 2020, 2:17 p.m.

Panel Version: 3.580

Created: 4 Dec 2020, 2:17 p.m.
Last Modified: 4 Dec 2020, 2:17 p.m.
Panel version: 3.580

Zornitza Stark (Australian Genomics)

I don't know

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Created: 4 Nov 2020, 4:34 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental disorder

Publications

33057194

Created: 4 Nov 2020, 4:34 a.m.

Panel version: 3.510

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Amber

Phenotypes

autism spectrum disorder, MONDO:0005258
neurodevelopmental disorder, MONDO:0700092

Tags

watchlist

OMIM

612064

Clinvar variants

Variants in GIGYF1

Penetrance

None

Publications

Panels with this gene