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Relevance to Autism

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012).

Molecular Function

This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs. Controls the endosome-to-Golgi trafficking of furin and mannose-6-phosphate receptor by connecting the acidic-cluster-containing cytoplasmic domain of these molecules with the adapter-protein complex-1 (AP-1) of endosomal clathrin-coated membrane pits.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Clinical delineation of the PACS1-related syndrome-Report on 19 patients.
ID
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID
Support
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
DD, ID, epilepsy/seizures
Stereotypy
Support
DD, epilepsy/seizures
Support
Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.
DD, ID
Epilepsy/seizures, ASD
Support
Support
Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
ID
Support
A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies
ASD, DD, ID, epilepsy/seizures
Support
DD, BPD
SAD, depression
Support
Schuurs-Hoeijmakers Syndrome ( PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review
Schuurs-Hoeijmakers syndrome, DD, ID
ASD, epilepsy/seizures, stereotypy
Support
Integrating de novo and inherited variants in 42
ASD
Support
DD, epilepsy/seizures
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Comprehensive genome sequencing analyses identify novel gene mutations and copy number variations associated with infant developmental delay or intellectual disability (DD/ID)
ID
Support
Schuurs-Hoeijmakers syndrome
Support
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.
ASD, DD
Support
Rare variants in the outcome of social skills group training for autism
ASD
Support
Schuurs-Hoeijmakers syndrome
Recent Recommendation
PACS1-Neurodevelopmental disorder: clinical features and trial readiness
Schuurs-Hoeijmakers syndrome
ASD, epilepsy/seizures

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN803R001 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R002 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R003 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R004 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R005 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R006 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R007 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R008 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R009 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R010 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R011 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R012 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R013 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R014 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R015 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R016 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R017 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R018 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R019 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R020 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R021 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R022 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R023 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R024 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R025 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R026 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R027 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R028 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 Unknown 
  
  
 GEN803R029 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R030 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R031 
 missense_variant 
 c.560C>T 
 p.Ala187Val 
 Familial 
 Paternal 
 Simplex 
 GEN803R032 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 Unknown 
  
  
 GEN803R033 
 missense_variant 
 c.2126G>A 
 p.Arg709Gln 
 De novo 
  
 Simplex 
 GEN803R034 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R035 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R036 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R037 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R038 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R039 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R040 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R041 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
 Simplex 
 GEN803R042 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
 Simplex 
 GEN803R043 
 stop_gained 
 c.115C>T 
 p.Gln39Ter 
 Unknown 
  
  
 GEN803R044 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
 Simplex 
 GEN803R045 
 inframe_insertion 
 c.119_121dup 
 p.Gln40dup 
 De novo 
  
  
 GEN803R046 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R047 
 synonymous_variant 
 c.1545G>A 
 p.Glu515%3D 
 De novo 
  
  
 GEN803R048 
 synonymous_variant 
 c.1545G>A 
 p.Glu515%3D 
 De novo 
  
 Simplex 
 GEN803R049 
 missense_variant 
 c.1622C>T 
 p.Thr541Met 
 De novo 
  
 Multiplex 
 GEN803R050 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 De novo 
  
  
 GEN803R051 
 missense_variant 
 c.755C>T 
 p.Ser252Phe 
 Familial 
 Maternal 
 Simplex 
 GEN803R052 
 frameshift_variant 
 c.135_136del 
 p.Thr46AlafsTer73 
 Familial 
 Maternal 
 Multiplex 
 GEN803R053 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 Unknown 
  
 Simplex 
  et al.  
 GEN803R054 
 missense_variant 
 c.607C>T 
 p.Arg203Trp 
 Unknown 
  
  
  et al.  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion-Duplication
 1
 
11
Deletion-Duplication
 18
 

Model Summary

Expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells.

References

Type
Title
Author, Year
Primary
Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.

Z_PACS1A_1_C.607T [P.TRP203]

Model Type: Genetic
Model Genotype: Wild type
Mutation: 50pg human mutant PACS1 mRNA with with p.Arg203Trp substitution was injected into 2- to 4-cell-stage zebrafish embryos. Also, wild-type (control) or mutant RNA was injected in 2- to 4-cell-stage sox10::eGFP transgenic zebrafish embryos, which express green fluorescent protein (GFP) in cranial neural crest cells.
Allele Type: knockdown
Strain of Origin: Not specified
Genetic Background: Not specified
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: 23159249

Z_PACS1A_1_C.607T [P.TRP203]

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal migration1
Decreased
Description: Embryos overexpressing mutant PACS1 showed a significant reduction in migration of neural crest cells in the anterior embryo compared to controls.
 Immunostaining
 4 dpf
Skeletal development: craniofacial1
Abnormal
Description: Embryos overexpressing mutant PACS1 showed a significant reduction in cranial cartilaginous structures at the ventral aspect compared to controls.
Exp Paradigm: Alcian Blue staining
 Immunostaining
 4 dpf
Gene expression1
Decreased
Description: Embryos overexpressing mutant PACS1 showed a significant reduction in the neural crest marker, sox10:GFP transcript, compared to controls.
 Quantitative pcr (qrt-pcr)
 Unreported
Gene expression1
 No change
 Quantitative pcr (qrt-pcr)
 Unreported
Neuronal migration1
 No change
 Immunostaining
 4 dpf
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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