Human Gene Module / Chromosome 1 / USH2A

USH2Ausherin

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
24 / 0
Aliases
USH2A, RP39,  US2,  USH2,  dJ1111A8.1
Associated Syndromes
-
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to USH2A (10 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 -
7 Support - Chen S et al. (2021) Yes DD, ID
8 Support - Zhou X et al. (2022) Yes -
9 Support - Tuncay IO et al. (2023) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.565C>T p.Arg189Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.9273A>G p.Thr3091%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3158-8T>C - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.10042A>C p.Ile3348Leu missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.6224G>A p.Trp2075Ter stop_gained Familial - Simplex 31209396 Doan RN , et al. (2019)
c.12714T>G p.Tyr4238Ter stop_gained Familial - Simplex 31209396 Doan RN , et al. (2019)
c.1479dup p.Tyr494LeufsTer4 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3973A>G p.Thr1325Ala missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4492C>G p.Pro1498Ala missense_variant Familial Paternal - 34800434 Chen S et al. (2021)
c.7616C>T p.Pro2539Leu missense_variant Familial Paternal - 34800434 Chen S et al. (2021)
c.4663G>A p.Gly1555Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.10931C>T p.Thr3644Met missense_variant Familial Maternal - 34800434 Chen S et al. (2021)
c.4388T>C p.Leu1463Ser missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.7643T>G p.Met2548Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.11146C>A p.Gln3716Lys missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.11978G>A p.Gly3993Asp missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.4492C>G p.Pro1498Ala missense_variant Familial Paternal Simplex 31031587 Xiong J , et al. (2019)
c.7616C>T p.Pro2539Leu missense_variant Familial Maternal Simplex 31031587 Xiong J , et al. (2019)
c.2809+1G>C - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.10931C>T p.Thr3644Met missense_variant Familial Maternal Simplex 31031587 Xiong J , et al. (2019)
c.15297+1G>C - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2300del p.Glu767GlyfsTer21 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1111_1112del p.Ile371PhefsTer3 frameshift_variant Familial Paternal Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
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
2

Strong Candidate

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: 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

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).

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).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019] [Recessive gene disruptions in autism spectrum disorder.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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