Human Gene Module / Chromosome 6 / HLA-G

HLA-Gmajor histocompatibility complex, class I, G

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
0 / 3
Aliases
HLA-G, MHC-G
Associated Syndromes
-
Chromosome Band
6p22.1
Associated Disorders
-
Relevance to Autism

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017).

Molecular Function

Involved in the presentation of foreign antigens to the immune system. Plays a role in maternal tolerance of the fetus by mediating protection from the deleterious effects of natural killer cells, cytotoxic T-lymphocytes, macrophages and mononuclear cells.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to HLA-G (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary An HLA-G(?)14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders Guerini FR , et al. (2014) Yes -
2 Support HLA-G?14bp Insertion and the KIR2DS1-HLAC2 Complex Impact on Behavioral Impairment in Children with Autism Spectrum Disorders Guerini FR , et al. (2017) Yes -
3 Positive Association HLA-G coding region polymorphism is skewed in autistic spectrum disorders Guerini FR , et al. (2017) Yes -
4 Positive Association HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study Guerini FR , et al. (2019) Yes -
Rare Variants  

No rare variants reported.

Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - allele - - - 30763769 Guerini FR , et al. (2019)
c.459delC p.Leu154Cysfs frameshift_variant - - - 28923404 Guerini FR , et al. (2017)
c.*65_*66insATTTGTTCATGCCT - 3_prime_UTR_variant - - - 25451607 Guerini FR , et al. (2014)
SFARI Gene score
2

Strong Candidate

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017). HLA-G allele association with ASD was also observed in a cohort of 100 Sardinian children with ASD, their mothers and unaffected siblings, with the HLA-G*01:03 allele being more common in ASD groups compared to controls (pc=1.0E-03; odds ratio 3.5, 95% CI 1.8-6.8).

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

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017). HLA-G allele association with ASD was also observed in a cohort of 100 Sardinian children with ASD, their mothers and unaffected siblings, with the HLA-G*01:03 allele being more common in ASD groups compared to controls (pc=1.0E-03; odds ratio 3.5, 95% CI 1.8-6.8).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017). HLA-G allele association with ASD was also observed in a cohort of 100 Sardinian children with ASD, their mothers and unaffected siblings, with the HLA-G*01:03 allele being more common in ASD groups compared to controls (pc=1.0E-03; odds ratio 3.5, 95% CI 1.8-6.8).

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

Decreased from 4 to 4

Description

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017). HLA-G allele association with ASD was also observed in a cohort of 100 Sardinian children with ASD, their mothers and unaffected siblings, with the HLA-G*01:03 allele being more common in ASD groups compared to controls (pc=1.0E-03; odds ratio 3.5, 95% CI 1.8-6.8).

Reports Added
[HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.2019]
10/1/2017
icon
4

Increased from to 4

Description

Evaluation of a 14bp insertion/deletion polymorphism (14bp+) in the 3'UTR of the HLA-G gene in a cohort of Italian families with ASD children showed that the frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p < 0.05 in all cases), and that the 14bp+ allele was more frequently transmitted to ASD children and preferentially not transmitted to non-ASD siblings [p=0.02, Odds ratio 2.6 (95% CI 1.1-6.4)] (Guerini et al., 2015). Evaluation of allelic polymorphism in exons 2, 3, and 4 in the HLA-G gene in a cohort of Italian ASD children, their mothers, and unaffected siblings, as well as in a cohort of combined controls, determined that the HLA-G*01:05N polymorphism was significantly more frequently observed in ASD children compared to combined controls (corrected P-value 5.0E-03; OR 7.3, 95% CI 2.4-26.5) (Guerini et al., 2017).

Krishnan Probability Score

Score 0.5633843978054

Ranking 1292/25841 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 9.5487062936644E-8

Ranking 15694/18225 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 0.94413731617537

Ranking 15958/18665 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 -0.46884890689766

Ranking 18977/20870 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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