Human Gene Module / Chromosome X / SSR4

SSR4signal sequence receptor subunit 4

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
3 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
-
Relevance to Autism

De novo likely loss-of-function variants in the SSR4 gene have been identified in ASD probands of East Asian ancestry (Takata et al., 2018; Miyake et al., 2023; Wu et al., 2024). Johnsen et al., 2024 reported that behavioral issues were described in 46% (5/11) of individuals diagnosed with SSR4-CDG, including autistic features, reduced impulse control and aggressive behavior (including auto-aggression), and stereotypies.

Molecular Function

This gene encodes the delta subunit of the translocon-associated protein complex which is involved in translocating proteins across the endoplasmic reticulum membrane. The encoded protein is located in the Xq28 region and is arranged in a compact head-to-head manner with the isocitrate dehydrogenase 3 (NAD+) gamma gene and both genes are driven by a CpG-embedded bidirectional promoter. Hemizygous mutations in the SSR4 gene are responsible for congenital disorder of glycosylation type Iy (CDG1Y; OMIM 300934).

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Human
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SFARI Genomic Platforms
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Reports related to SSR4 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
2 Support - Miyake N et al. (2023) Yes -
3 Primary - Ruohao Wu et al. (2024) Yes -
4 Support - Christin Johnsen et al. () No Autistic behavior, stereotypy
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.184C>T p.Gln62Ter stop_gained De novo - Simplex 36973392 Miyake N et al. (2023)
c.184C>T p.Gln62Ter stop_gained De novo - Simplex 29346770 Takata A , et al. (2018)
c.303dup p.Tyr113LeufsTer2 frameshift_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49501643023399

Ranking 3275/25841 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 0.8067922117507

Ranking 3888/18225 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 0.9090973178953

Ranking 7410/18665 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 -0.03777940565136

Ranking 9966/20870 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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