Human Gene Module / Chromosome 11 / PACS1

PACS1phosphofurin acidic cluster sorting protein 1

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
33 / 0
Aliases
PACS1, MRD17
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11q13.1-q13.2
Associated Disorders
EPS, EP, ASD
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.

Reports related to PACS1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Schuurs-Hoeijmakers JH , et al. (2012) No -
2 Primary Clinical delineation of the PACS1-related syndrome-Report on 19 patients. Schuurs-Hoeijmakers JH , et al. (2016) No ASD (6/19 cases)
3 Support Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures. Stern D , et al. (2017) No Epilepsy/seizures (5/7 cases), ASD (2/7 cases)
4 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
5 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.607C>T p.Arg203Trp missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.560C>T p.Ala187Val missense_variant Familial Paternal Simplex 28628100 Geisheker MR , et al. (2017)
c.607C>T p.Arg203Trp missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
G>A p.Arg245Gln missense_variant De novo - - 28714951 Lim ET , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

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). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

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."

07-01-2017
S

Initial score established: S

Description

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). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

CNVs associated with PACS1(1 CNVs)
11q13.1-q13.2 1 Deletion-Duplication 2  /  3
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