USP9Xubiquitin specific peptidase 9 X-linked
Autism Reports / Total Reports
6 / 19Rare Variants / Common Variants
73 / 0Aliases
USP9X, DFFRX, FAF, FAM, MRX99, MRXS99FAssociated Syndromes
-Chromosome Band
Xp11.4Associated Disorders
EP, ASD, EPSRelevance 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
SFARI Genomic Platforms
Reports related to USP9X (19 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 | - | Omri Bar et al. (2024) | Yes | Learning disability |
17 | Support | - | Tamam Khalaf et al. (2024) | No | - |
18 | Support | - | Shenglan Li et al. (2024) | Yes | - |
19 | Support | - | Axel Schmidt et al. (2024) | No | - |
Rare Variants (73)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | copy_number_loss | De novo | - | - | 26833328 | Reijnders MR , et al. (2016) | |
- | - | copy_number_loss | De novo | - | Simplex | 26833328 | Reijnders MR , et al. (2016) | |
c.1315-284G>T | - | intron_variant | De novo | - | - | 38593811 | Shenglan Li et al. (2024) | |
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.1774C>T | p.Arg592Ter | stop_gained | Unknown | - | - | 38438125 | Tamam Khalaf et al. (2024) | |
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.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.5014A>G | p.Arg1672Gly | missense_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
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.5686C>T | p.Arg1896Cys | missense_variant | Familial | Maternal | Simplex | 38256266 | Omri Bar et al. (2024) | |
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.2144_2155delinsGTCTGGA | p.Ile715SerfsTer5 | frameshift_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
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
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 criteriaWe 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.
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
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
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.
4/1/2020
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.
10/1/2019
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]
ExAC Score
Score 0.99999999997644
Ranking 54/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.93115796288731
Ranking 11623/18665 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.43629499048955
Ranking 1071/20870 scored genes
[Show Scoring Methodology]