Human Gene Module / Chromosome 1 / USH2A

USH2Ausherin

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
9 / 0
Aliases
USH2A, RP39,  US2,  USH2,  dJ1111A8.1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
1q41
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the USH2A gene were identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012) and the Simons Simplex Collection (Iossifov et al., 2014); one of these variants was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (/571 observed vs. /84,448 expected; hypergeometric P-value of 0.023). Biallelic variants in the USH2A gene have also been identified in individuals diagnosed with ASD (Xiong et al., 2019; Doan et al., 2019).

Molecular Function

This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa.

Reports related to USH2A (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
4 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes -
5 Support Recessive gene disruptions in autism spectrum disorder. Doan RN , et al. (2019) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.10042A>C p.Ile3348Leu missense_variant De novo NA - 28714951 Lim ET , et al. (2017)
c.4388T>C p.Leu1463Ser missense_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.7643T>G p.Met2548Arg missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.6224G>A p.Trp2075Ter stop_gained Familial Maternal and paternal Simplex 31209396 Doan RN , et al. (2019)
c.12714T>G p.Tyr4238Ter stop_gained Familial Maternal and paternal Simplex 31209396 Doan RN , et al. (2019)
c.2300del p.Glu767GlyfsTer21 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.4492C>G p.Pro1498Ala missense_variant Familial Maternal and paternal Simplex 31031587 Xiong J , et al. (2019)
c.10931C>T p.Thr3644Met missense_variant Familial Maternal and paternal Simplex 31031587 Xiong J , et al. (2019)
c.10596_10597insAT p.Tyr3533IlefsTer18 frameshift_variant Familial Maternal Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Two de novo missense variants in the USH2A gene were identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012) and the Simons Simplex Collection (Iossifov et al., 2014); one of these variants was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (/571 observed vs. /84,448 expected; hypergeometric P-value of 0.023).

Score Delta: Decreased from 4 to 3

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants in the USH2A gene were identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012) and the Simons Simplex Collection (Iossifov et al., 2014); one of these variants was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (/571 observed vs. /84,448 expected; hypergeometric P-value of 0.023).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the USH2A gene were identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012) and the Simons Simplex Collection (Iossifov et al., 2014); one of these variants was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (/571 observed vs. /84,448 expected; hypergeometric P-value of 0.023).

7/1/2017
icon
4

Increased from to 4

Description

Two de novo missense variants in the USH2A gene were identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012) and the Simons Simplex Collection (Iossifov et al., 2014); one of these variants was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (/571 observed vs. /84,448 expected; hypergeometric P-value of 0.023).

Krishnan Probability Score

Score 0.49375401756537

Ranking 3984/25841 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 3.6810033620746E-43

Ranking 18208/18225 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 0.95083064952526

Ranking 18645/18665 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 -0.37018617141376

Ranking 18050/20870 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.
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