Human Gene Module / Chromosome X / USP9X

USP9Xubiquitin specific peptidase 9 X-linked

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
5 / 17
Rare Variants / Common Variants
70 / 0
Aliases
USP9X, DFFRX,  FAF,  FAM,  MRX99,  MRXS99F
Associated Syndromes
-
Chromosome Band
Xp11.4
Associated Disorders
EP, ASD, EPS
Relevance to Autism

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

Molecular Function

This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to USP9X (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth Homan CC , et al. (2014) No ASD
2 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) No -
3 Support Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase Paemka L , et al. (2015) No -
4 Support De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations Reijnders MR , et al. (2016) No -
5 Recent Recommendation Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor ? Signaling Johnson BV , et al. (2019) No ASD
6 Support Novel USP9X variants in two patients with X-linked intellectual disability Tsurusaki Y , et al. (2019) No -
7 Recent Recommendation Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development Yoon S , et al. (2019) No -
8 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
9 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
10 Support Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder Wang L et al. (2020) Yes -
11 Support - Jolly LA et al. (2020) No Epilepsy/seizures, poor eye contact
12 Support - Hu C et al. (2022) Yes -
13 Support - Chen Y et al. (2021) No -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Spataro N et al. (2023) No Autistic features
16 Support - et al. () Yes Learning disability
17 Support - et al. () No -
Rare Variants   (70)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1774C>T p.Arg592Ter stop_gained Unknown - - 38438125 et al. ()
- - copy_number_loss De novo - - 26833328 Reijnders MR , et al. (2016)
- - copy_number_loss De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.1140G>A p.Trp380Ter stop_gained De novo - - 33298948 Jolly LA et al. (2020)
c.461G>A p.Arg154His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.745G>A p.Val249Ile missense_variant De novo - - 33004838 Wang T et al. (2020)
c.367G>A p.Gly123Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3066G>A p.Trp1022Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.1396G>A p.Asp466Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2081G>A p.Arg694His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3658C>T p.Arg1220Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5975G>A p.Arg1992Gln missense_variant De novo - - 33004838 Wang T et al. (2020)
c.6236G>A p.Arg2079His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.671T>C p.Leu224Pro missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.1201C>T p.Arg401Ter stop_gained De novo - - 31666975 Tsurusaki Y , et al. (2019)
c.3028-2A>G - splice_site_variant De novo - - 26833328 Reijnders MR , et al. (2016)
c.1073T>A p.Val358Asp missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.1303T>C p.Trp435Arg missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.2554C>T p.Arg852Ter stop_gained De novo - - 26833328 Reijnders MR , et al. (2016)
c.3664G>C p.Ala1222Pro missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.3986G>A p.Arg1329His missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.5053G>A p.Asp1685Asn missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.5405A>G p.Tyr1802Cys missense_variant De novo - - 33298948 Jolly LA et al. (2020)
c.1986-1G>T - splice_site_variant De novo - Simplex 24690944 Brett M , et al. (2014)
c.3034T>C p.Ser1012Pro missense_variant De novo - - 25763846 Paemka L , et al. (2015)
c.5669G>A p.Gly1890Glu missense_variant Unknown - - 25763846 Paemka L , et al. (2015)
c.4726T>A p.Tyr1576Asn missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.392T>A p.Ile131Asn missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.642C>T p.Arg215Ter stop_gained Familial Maternal - 33298948 Jolly LA et al. (2020)
c.2464C>T p.Arg822Cys missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.2912A>G p.Asn971Ser missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.4086_4086+1dup - frameshift_variant De novo - - 26833328 Reijnders MR , et al. (2016)
c.82dup p.Leu28ProfsTer10 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.4406C>T p.Pro1469Leu missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.4718A>T p.Gln1573Leu missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.5216C>A p.Thr1739Asn missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.5603T>A p.Val1868Glu missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.6034T>A p.Phe2012Ile missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.6254G>A p.Arg2085His missense_variant De novo - - 31443933 Johnson BV , et al. (2019)
c.5686C>T p.Arg1896Cys missense_variant Familial Maternal Simplex 38256266 et al. ()
c.2902A>C p.Ile968Leu missense_variant Familial Maternal - 35741772 Hu C et al. (2022)
c.2897C>A p.Thr966Lys missense_variant Unknown - Unknown 35873028 Chen Y et al. (2021)
c.2078A>T p.Asp693Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4147_4149del p.Leu1383del inframe_deletion De novo - - 33298948 Jolly LA et al. (2020)
c.5642_5644del p.Tyr1881del inframe_deletion De novo - - 33298948 Jolly LA et al. (2020)
c.2445C>T p.Phe815%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1111C>T p.Arg371Ter stop_gained De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.3763C>T p.Gln1255Ter stop_gained De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.3804T>A p.Tyr1268Ter stop_gained De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.1603dup p.Ile535AsnfsTer11 frameshift_variant De novo - - 33298948 Jolly LA et al. (2020)
c.6278T>A p.Leu2093His missense_variant Unknown - Simplex 24607389 Homan CC , et al. (2014)
c.10A>G p.Thr4Ala missense_variant Familial Maternal Simplex 33023636 Wang L et al. (2020)
c.5053G>A p.Asp1685Asn missense_variant Familial Maternal - 33298948 Jolly LA et al. (2020)
c.5290G>A p.Glu1764Lys missense_variant Familial Maternal - 33298948 Jolly LA et al. (2020)
c.5997_5998del p.Met1999IlefsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.437G>A p.Arg146Lys missense_variant Familial Maternal Simplex 33023636 Wang L et al. (2020)
c.5078T>G p.Leu1693Trp missense_variant De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.1881G>C p.Met627Ile missense_variant Familial Maternal Simplex 33023636 Wang L et al. (2020)
c.4055dup p.Phe1353LeufsTer18 frameshift_variant De novo - - 26833328 Reijnders MR , et al. (2016)
c.235A>G p.Ile79Val missense_variant Familial Maternal Simplex 31443933 Johnson BV , et al. (2019)
c.6469C>A p.Leu2157Ile missense_variant Familial Maternal Simplex 24607389 Homan CC , et al. (2014)
c.3410C>T p.Pro1137Leu missense_variant Familial Maternal Unknown 32277047 Chevarin M et al. (2020)
c.4054_4058del p.Phe1352HisfsTer17 frameshift_variant De novo - - 31666975 Tsurusaki Y , et al. (2019)
c.7495_7509del p.Asp2499_Glu2503del inframe_deletion De novo - - 26833328 Reijnders MR , et al. (2016)
c.2644_2645insA p.Arg882GlnfsTer3 frameshift_variant De novo - - 26833328 Reijnders MR , et al. (2016)
c.6697T>C p.Ser2233Pro missense_variant Familial Maternal Simplex 31443933 Johnson BV , et al. (2019)
c.2087C>T p.Ala696Val missense_variant Familial Maternal Multiplex 31443933 Johnson BV , et al. (2019)
c.1156del p.Met386TrpfsTer13 frameshift_variant De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.3709del p.Cys1237ValfsTer2 frameshift_variant De novo - Simplex 26833328 Reijnders MR , et al. (2016)
c.7574del p.Gln2525ArgfsTer18 frameshift_variant Familial Maternal Multi-generational 24607389 Homan CC , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
S
icon
1S

Increased from S to 1S

Description

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

1/1/2021
S
icon
S

Increased from S to S

Description

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

Reports Added
[Missense variant contribution to USP9X-female syndrome2020]
4/1/2020
S
icon
S

Increased from S to S

Description

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
10/1/2019
icon
S

Increased from to S

New Scoring Scheme
Description

USP9X was initially associated with X-linked intellectual disability following the identification of pathogenic USP9X variants in five affected males from three families in Homan et al., 2014. Phenotypic review of males with likely pathogenic variants in the USP9X gene (including affected individuals from Homan et al., 2014) identified a neurodevelopmental disorder characterized by developmental delay, delayed or absent speech, motor problems, brain malformations, behavioral problems (predominantly autistic and obsessive behaviors), visual system defects, growth retardation, joint hypermobility, and gastroenterological disturbances (Johnson et al., 2019). De novo loss-of-function variants in USP9X were found to cause a female-specific syndrome characterized by developmental delay/intellectual disability, dysmorphic facial features, short stature, and distinct congenital malformations in Reijnders et al., 2016.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.57021909816089

Ranking 950/25841 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 0.99999999997644

Ranking 54/18225 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 0.93115796288731

Ranking 11623/18665 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 0.43629499048955

Ranking 1071/20870 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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