Human Gene Module / Chromosome 3 / GBE1

GBE11,4-alpha-glucan branching enzyme 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3p12.2
Associated Disorders
-
Relevance to Autism

Fanjul-Fernandez et al., 2021 studied a large multi-generational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP) and identified a rare heterozygous missense variant in the GBE1 gene (NM_000158.4:c.176T>C;p.Ile59Thr) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP and none of the four tested unaffected individuals. Furthermore, subsequent genotyping of a community-acquired cohort of 389 individuals with ASD in this report identified three additional probands with the p.Ile59Thr missense variant in GBE1; cascade analysis demonstrated that this variant was present in eleven of thirteen individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. Functional analysis of the p.Ile59Thr variant demonstrated a decrease in steady state levels of mutant protein in transiently transfected cells compared to wild-type protein. Lastly, this report demonstrated while the GBE1 variant was not enriched in the combined UK10K ASD cohorts of European ancestry (16/604 ASD cases vs. 189/7935 European controls, OR 1.11, P = 0.68), heterozygous GBE1 deletions were overrepresented in a cohort of cases with ASD and other neurodevelopmental disorders (6 deletions in 29,085 cases vs. none in controls; p = 0.045), as well as in a cohort of ASD cases from the Autism Genome Project (11 deletions in 7,745 cases vs. one in 21,694 alleles in gnomAD). Inherited nonsense variants in the GBE1 gene had previously been identified in ASD probands from the iHART cohort in Ruzzo et al., 2019.

Molecular Function

The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease).

External Links
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Reports related to GBE1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
2 Primary - Fanjul-Fernández M et al. (2021) Yes -
3 Support - N.Y.) (07/2) No -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Omri Bar et al. (2024) Yes ID
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.773C>A p.Ala258Glu missense_variant De novo - - 35901164 N.Y.) (07/2)
c.1137A>C p.Glu379Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.480G>A p.Trp160Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.176T>C p.Ile59Thr missense_variant Familial Maternal Simplex 38256266 Omri Bar et al. (2024)
c.1570C>T p.Arg524Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1788G>A p.Trp596Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1883A>G p.His628Arg missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.176T>C p.Ile59Thr missense_variant Familial Maternal Simplex 34633740 Fanjul-Fernández M et al. (2021)
c.176T>C p.Ile59Thr missense_variant Familial Maternal Multiplex 34633740 Fanjul-Fernández M et al. (2021)
c.176T>C p.Ile59Thr missense_variant Familial - Multi-generational 34633740 Fanjul-Fernández M et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.40208266727273

Ranking 23338/25841 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 1.1785654369979E-13

Ranking 17493/18225 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 0.86049148652902

Ranking 3869/18665 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 -0.48080441694915

Ranking 19084/20870 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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