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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

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth.
X-linked mental retardation-99 (MRX99)
ASD
Support
Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability
ID
Marfanoid habitus
Support
Novel USP9X variants in two patients with X-linked intellectual disability.
Female-restricted X-linked syndromic mental retard
Support
De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations.
Female-restricted X-linked syndromic mental retard
Support
Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.
Epilepsy/seizures
Support
Missense variant contribution to USP9X-female syndrome
Female-restricted X-linked syndromic mental retard
Epilepsy/seizures, poor eye contact
Support
Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...
Female-restricted X-linked syndromic mental retard
Support
Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder
ASD
Support
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
ASD, DD
Recent Recommendation
Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development.
Recent Recommendation
Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor Signaling.
X-linked mental retardation-99 (MRX99)
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1126R001 
 missense_variant 
 c.6278T>A 
 p.Leu2093His 
 Unknown 
  
 Simplex 
 GEN1126R002 
 missense_variant 
 c.6469C>A 
 p.Leu2157Ile 
 Familial 
 Maternal 
 Simplex 
 GEN1126R003 
 frameshift_variant 
 c.7574del 
 p.Gln2525ArgfsTer18 
 Familial 
 Maternal 
 Multi-generational 
 GEN1126R004 
 missense_variant 
 c.3034T>C 
 p.Ser1012Pro 
 De novo 
 NA 
  
 GEN1126R005 
 missense_variant 
 c.5669G>A 
 p.Gly1890Glu 
 Unknown 
  
  
 GEN1126R006 
 splice_site_variant 
 c.1986-1G>T 
  
 De novo 
 NA 
 Simplex 
 GEN1126R007 
 stop_gained 
 c.2554C>T 
 p.Arg852Ter 
 De novo 
 NA 
  
 GEN1126R008 
 stop_gained 
 c.3804T>A 
 p.Tyr1268Ter 
 De novo 
 NA 
 Simplex 
 GEN1126R009 
 splice_site_variant 
 c.3028-2A>G 
  
 De novo 
 NA 
  
 GEN1126R010 
 frameshift_variant 
 c.2644_2645insA 
 p.Arg882GlnfsTer3 
 De novo 
 NA 
  
 GEN1126R011 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN1126R012 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN1126R013 
 missense_variant 
 c.5078T>G 
 p.Leu1693Trp 
 De novo 
 NA 
 Simplex 
 GEN1126R014 
 frameshift_variant 
 c.4086_4086+1dup 
  
 De novo 
 NA 
  
 GEN1126R015 
 inframe_deletion 
 c.7495_7509del 
 p.Asp2499_Glu2503del 
 De novo 
 NA 
  
 GEN1126R016 
 stop_gained 
 c.3763C>T 
 p.Gln1255Ter 
 De novo 
 NA 
 Simplex 
 GEN1126R017 
 stop_gained 
 c.1111C>T 
 p.Arg371Ter 
 De novo 
 NA 
 Simplex 
 GEN1126R018 
 frameshift_variant 
 c.1156del 
 p.Met386TrpfsTer13 
 De novo 
 NA 
 Simplex 
 GEN1126R019 
 frameshift_variant 
 c.3709del 
 p.Cys1237ValfsTer2 
 De novo 
 NA 
 Simplex 
 GEN1126R020 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN1126R021 
 frameshift_variant 
 c.4055dup 
 p.Phe1353LeufsTer18 
 De novo 
 NA 
  
 GEN1126R022 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN1126R023 
 missense_variant 
 c.235A>G 
 p.Ile79Val 
 Familial 
 Maternal 
 Simplex 
 GEN1126R024 
 missense_variant 
 c.392T>A 
 p.Ile131Asn 
 De novo 
 NA 
  
 GEN1126R025 
 missense_variant 
 c.2087C>T 
 p.Ala696Val 
 Familial 
 Maternal 
 Multiplex 
 GEN1126R026 
 missense_variant 
 c.2464C>T 
 p.Arg822Cys 
 De novo 
 NA 
  
 GEN1126R027 
 missense_variant 
 c.2912A>G 
 p.Asn971Ser 
 De novo 
 NA 
  
 GEN1126R028 
 missense_variant 
 c.4406C>T 
 p.Pro1469Leu 
 De novo 
 NA 
  
 GEN1126R029 
 missense_variant 
 c.4718A>T 
 p.Gln1573Leu 
 De novo 
 NA 
  
 GEN1126R030 
 missense_variant 
 c.5216C>A 
 p.Thr1739Asn 
 De novo 
 NA 
  
 GEN1126R031 
 missense_variant 
 c.5603T>A 
 p.Val1868Glu 
 De novo 
 NA 
  
 GEN1126R032 
 missense_variant 
 c.6034T>A 
 p.Phe2012Ile 
 De novo 
 NA 
  
 GEN1126R033 
 missense_variant 
 c.6254G>A 
 p.Arg2085His 
 De novo 
 NA 
  
 GEN1126R034 
 missense_variant 
 c.6697T>C 
 p.Ser2233Pro 
 Familial 
 Maternal 
 Simplex 
 GEN1126R035 
 frameshift_variant 
 c.4054_4058del 
 p.Phe1352HisfsTer17 
 De novo 
 NA 
  
 GEN1126R036 
 stop_gained 
 c.1201C>T 
 p.Arg401Ter 
 De novo 
 NA 
  
 GEN1126R037 
 missense_variant 
 c.3410C>T 
 p.Pro1137Leu 
 Familial 
 Maternal 
 Unknown 
 GEN1126R038 
 frameshift_variant 
 c.82dup 
 p.Leu28ProfsTer10 
 De novo 
 NA 
  
 GEN1126R039 
 missense_variant 
 c.745G>A 
 p.Val249Ile 
 De novo 
 NA 
  
 GEN1126R040 
 missense_variant 
 c.5975G>A 
 p.Arg1992Gln 
 De novo 
 NA 
  
 GEN1126R041 
 frameshift_variant 
 c.5997_5998del 
 p.Met1999IlefsTer2 
 Unknown 
  
  
 GEN1126R042 
 missense_variant 
 c.461G>A 
 p.Arg154His 
 Unknown 
  
  
 GEN1126R043 
 missense_variant 
 c.6236G>A 
 p.Arg2079His 
 Unknown 
  
  
 GEN1126R044 
 missense_variant 
 c.2081G>A 
 p.Arg694His 
 Unknown 
  
  
 GEN1126R045 
 missense_variant 
 c.1396G>A 
 p.Asp466Asn 
 Unknown 
  
  
 GEN1126R046 
 missense_variant 
 c.3658C>T 
 p.Arg1220Cys 
 Unknown 
  
  
 GEN1126R047 
 missense_variant 
 c.10A>G 
 p.Thr4Ala 
 Familial 
 Maternal 
 Simplex 
 GEN1126R048 
 missense_variant 
 c.437G>A 
 p.Arg146Lys 
 Familial 
 Maternal 
 Simplex 
 GEN1126R049 
 missense_variant 
 c.1881G>C 
 p.Met627Ile 
 Familial 
 Maternal 
 Simplex 
 GEN1126R050 
 missense_variant 
 c.671T>C 
 p.Leu224Pro 
 De novo 
 NA 
  
 GEN1126R051 
 missense_variant 
 c.1073T>A 
 p.Val358Asp 
 De novo 
 NA 
  
 GEN1126R052 
 missense_variant 
 c.1303T>C 
 p.Trp435Arg 
 De novo 
 NA 
  
 GEN1126R053 
 missense_variant 
 c.3664G>C 
 p.Ala1222Pro 
 De novo 
 NA 
  
 GEN1126R054 
 missense_variant 
 c.3986G>A 
 p.Arg1329His 
 De novo 
 NA 
  
 GEN1126R055 
 missense_variant 
 c.5053G>A 
 p.Asp1685Asn 
 Familial 
 Maternal 
  
 GEN1126R056 
 missense_variant 
 c.5053G>A 
 p.Asp1685Asn 
 De novo 
 NA 
  
 GEN1126R057 
 missense_variant 
 c.5405A>G 
 p.Tyr1802Cys 
 De novo 
 NA 
  
 GEN1126R058 
 inframe_deletion 
 c.5642_5644del 
 p.Tyr1881del 
 De novo 
 NA 
  
 GEN1126R059 
 stop_gained 
 c.1140G>A 
 p.Trp380Ter 
 De novo 
 NA 
  
 GEN1126R060 
 stop_gained 
 c.642C>T 
 p.Arg215Ter 
 Familial 
 Maternal 
  
 GEN1126R061 
 frameshift_variant 
 c.1603dup 
 p.Ile535AsnfsTer11 
 De novo 
 NA 
  
 GEN1126R062 
 missense_variant 
 c.5290G>A 
 p.Glu1764Lys 
 Familial 
 Maternal 
  
 GEN1126R063 
 inframe_deletion 
 c.4147_4149del 
 p.Leu1383del 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 30
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

No Animal Model Data Available

 

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