Human Gene Module / Chromosome 12 / SRRM4

SRRM4Serine/arginine repetitive matrix 4

Score
5
Hypothesized Criteria 5.1
Autism Reports / Total Reports
1 / 5
Rare Variants / Common Variants
1 / 0
Aliases
SRRM4, KIAA1853,  MU-MB-2.76,  nSR100
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
12q24.23
Associated Disorders
-
Relevance to Autism

Neural microexons, many of which are regulated by the neuronal-specific splicing factor nSR100/SRRM4, were found to be frequently dysregulated in the brains of individuals with ASD; this dysregulation was associated with reduced levels of nSR100 (Irimia et al., 2014). nSR100/Srrm4 haploinsufficiency in mice resulted in misregulated splicing patterns, autistic features such as sensory hypersensitivity and altered social behavior, and impaired synaptic transmission and excitability (Quesnel-Vallieres et al., 2016).

Molecular Function

SRRM4 promotes alternative splicing and inclusion of neural-specific exons in target mRNAs. This splicing factor is specifically required for neural cell differentiation.

Reports related to SRRM4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis. Raj B , et al. (2011) No -
2 Support A global regulatory mechanism for activating an exon network required for neurogenesis. Raj B , et al. (2014) No -
3 Primary A highly conserved program of neuronal microexons is misregulated in autistic brains. Irimia M , et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
5 Recent Recommendation Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders. Quesnel-Vallires M , et al. (2016) No -
Rare Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.217G>A p.Gly73Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
5

Hypothesized

5

Score Delta: Score remained at 5.1

5

Hypothesized

See all Category 5 Genes

Category 5.1 includes genes for which the only evidence comes from studies of model organisms, without statistical or genetic support in human studies.

1/1/2017
5
icon
5

Score remained at 5

Description

Neural microexons, many of which are regulated by the neuronal-specific splicing factor nSR100/SRRM4, were found to be frequently dysregulated in the brains of individuals with ASD; this dysregulation was associated with reduced levels of nSR100 (Irimia et al., 2014). nSR100/Srrm4 haploinsufficiency in mice resulted in misregulated splicing patterns, autistic features such as sensory hypersensitivity and altered social behavior, and impaired synaptic transmission and excitability (Quesnel-Vallieres et al., 2016).

7/1/2015
icon
5

Increased from to 5

Description

Neural microexons, many of which are regulated by the neuronal-specific splicing factor nSR100/SRRM4, were found to be frequently dysregulated in the brains of individuals with ASD; this dysregulation was associated with reduced levels of nSR100 (Irimia et al., 2014).

Krishnan Probability Score

Score 0.56902633088987

Ranking 1068/25841 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 0.41174762615471

Ranking 5909/18225 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 0.90628906019122

Ranking 7062/18665 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).
Zhang D Score

Score 0.44336832897643

Ranking 988/20870 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.
CNVs associated with SRRM4(1 CNVs)
12q24.23 5 Deletion-Duplication 10  /  29
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