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Relevance to Autism

An in-frame deletion variant in PHF8 was found to segregate with high-functioning autism without other clinical features in a multiplex ASD family (Nava et al., 2012). Mutations in this gene are associated with a syndromic form of X-linked intellectual disability (Siderius type X-linked syndromic mental retardation; OMIM 300263); behavioral abnormalities and stereotypic movements have been observed in some individuals with this disorder (Laumonnier et al., 2005; Abidi et al., 2007; Koivisto et al., 2007; Redin et al., 2014; Deciphering Developmental Disorders Study 2015). Sobering et al., 2022 presented 16 individuals with Siderious X-linked intellectual disability syndrome caused by loss-of-function variants in the PHF8 gene from 11 families and found that all affected individuals exhibited developmental delay, and all but two had borderline to severe intellectual disability, autism spectrum disorder (ASD) was reported in seven of these individuals.

Molecular Function

The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
ASD
ID
Support
Large-scale discovery of novel genetic causes of developmental disorders.
DD, ADHD
Microcephaly
Support
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
ID
Support
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
ASD, DD, ID
Support
Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate.
ID
Support
A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain
ASD
Support
A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate.
ID
Support
A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders
ASD, DD
Support
Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.
ID
Support
Characterization of intellectual disability and autism comorbidity through gene panel sequencing.
ID, ASD or autistic traits
Highly Cited
Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate.
ID
Recent Recommendation
Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology
DD, ID
ASD, ADHD, epilepsy/seizures
Recent Recommendation
JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN456R001 
 inframe_deletion 
 c.2904_2906del 
 p.Ser969del 
 Familial 
 Maternal 
 Multiplex 
 GEN456R002 
 splice_site_variant 
 del(ACAGGTCTTCCC) 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN456R003 
 stop_gained 
 c.631C>T 
 p.Arg211Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN456R004 
 stop_gained 
 c.529T>A 
 p.Ser177Thr 
 De novo 
  
  
 GEN456R005 
 missense_variant 
 c.836C>T 
 p.Phe279Ser 
 Familial 
 Maternal 
 Multiplex 
 GEN456R006 
 frameshift_variant 
 c.738dup 
 p.Arg247SerfsTer17 
 Familial 
 Maternal 
 Multi-generational 
 GEN456R007 
 splice_site_variant 
 c.1249+5G>C 
  
 Familial 
 Maternal 
 Simplex 
 GEN456R008 
 missense_variant 
 c.2794T>C 
 p.Cys932Arg 
 Familial 
 Maternal 
  
 GEN456R009 
 stop_gained 
 c.252C>A 
 p.Tyr84Ter 
 Familial 
 Maternal 
 Simplex 
 GEN456R010 
 missense_variant 
 c.2972A>G 
 p.Asn991Ser 
 Familial 
 Maternal 
 Simplex 
 GEN456R011 
 missense_variant 
 c.*1112G>C 
  
 Familial 
 Maternal 
  
 GEN456R012 
 missense_variant 
 c.*1101G>A 
  
 Unknown 
  
  
 GEN456R013 
 missense_variant 
 c.2475G>C 
 p.Glu825Asp 
 Unknown 
  
  
 GEN456R014 
 missense_variant 
 c.2239G>A 
 p.Glu747Lys 
 Familial 
 Maternal 
  
 GEN456R015 
 missense_variant 
 c.264C>A 
 p.Asn88Lys 
 Unknown 
  
  
 GEN456R016 
 missense_variant 
 c.124G>T 
 p.Val42Leu 
 Familial 
 Maternal 
  
 GEN456R017 
 inframe_deletion 
 c.2190_2192del 
 p.Leu731del 
 De novo 
  
 Simplex 
 GEN456R018 
 inframe_deletion 
  
 p.Gly316_Arg380del 
 Familial 
 Maternal 
  
 GEN456R019 
 splice_site_variant 
 c.704+1G>A 
  
 De novo 
  
 Simplex 
 GEN456R020 
 stop_gained 
 c.862C>T 
 p.Gln288Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN456R021 
 frameshift_variant 
 c.2104del 
 p.Glu702ArgfsTer163 
 Familial 
 Maternal 
 Simplex 
 GEN456R022 
 stop_gained 
 c.1027C>T 
 p.Gln343Ter 
 Familial 
 Maternal 
 Extended multiplex 
 GEN456R023 
 splice_site_variant 
 c.1731-2A>G 
  
 Familial 
 Maternal 
 Multiplex (monozygotic twins) 
 GEN456R024 
 splice_site_variant 
 c.1731-2A>G 
  
 Familial 
 Maternal 
 Simplex 
 GEN456R025 
 splice_site_variant 
 c.1627-1G>A 
  
 De novo 
  
  
 GEN456R026 
 frameshift_variant 
 c.846dup 
 p.His283SerfsTer3 
 Familial 
 Maternal 
  
 GEN456R027 
 frameshift_variant 
 c.2868dup 
 p.Thr957HisfsTer19 
 Familial 
 Maternal 
  
 GEN456R028 
 frameshift_variant 
 c.2073_2074insTG 
 p.Glu692TrpfsTer174 
 De novo 
  
 Simplex 
 GEN456R029 
 inframe_deletion 
 c.294-1820_597-603del 
  
 Familial 
 Maternal 
 Simplex 
 GEN456R030 
 missense_variant 
 c.143A>G 
 p.Tyr48Cys 
 Familial 
 Maternal 
  
 GEN456R031 
 missense_variant 
 c.257C>T 
 p.Thr86Met 
 Familial 
 Maternal 
 Multiplex 
 GEN456R032 
 missense_variant 
 c.808C>T 
 p.Arg270Cys 
 Familial 
 Maternal 
  
 GEN456R033 
 missense_variant 
 c.1150G>A 
 p.Glu384Lys 
 Familial 
 Maternal 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 25
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 2
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 21
 

No Animal Model Data Available


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ANAPC1 anaphase promoting complex subunit 1 64682 Q9H1A4 TAP; MS; IP/WB
Lim HJ , et al. 2013
ANAPC2 anaphase promoting complex subunit 2 29882 Q9UJX6 TAP; MS; IP/WB
Lim HJ , et al. 2013
ANAPC4 anaphase promoting complex subunit 4 29945 Q9UJX5 TAP; MS; IP/WB
Lim HJ , et al. 2013
ANAPC5 anaphase promoting complex subunit 5 51433 Q9UJX4 TAP; MS; IP/WB
Lim HJ , et al. 2013
ANAPC7 anaphase promoting complex subunit 7 51434 Q9UJX3 TAP; MS; IP/WB
Lim HJ , et al. 2013
APP amyloid beta (A4) precursor protein 351 P05067 Protein microarray
Olh J , et al. 2011
ASH2L ash2 (absent, small, or homeotic)-like (Drosophila) 9070 Q9UBL3 IP/WB
Feng W , et al. 2010
CCNA2 cyclin A2 890 P20248 IP; LC-MS/MS
Huttlin EL , et al. 2015
CDC16 cell division cycle 16 8881 Q13042 TAP; MS; IP/WB
Lim HJ , et al. 2013
CDC20 cell division cycle 20 991 Q12834 TAP; MS; IP/WB
Lim HJ , et al. 2013
CDC23 cell division cycle 23 8697 Q9UJX2 TAP; MS; IP/WB
Lim HJ , et al. 2013
CDC26 cell division cycle 26 246184 Q8NHZ8 TAP; MS; IP/WB
Lim HJ , et al. 2013
CDC27 cell division cycle 27 996 G3V1C4 TAP; MS; IP/WB
Lim HJ , et al. 2013
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
Dlg4 DLG4discs, large homolog 4 (Drosophila) 1742 P78352 Peptide microarray
Arbuckle MI , et al. 2010
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
FZR1 fizzy/cell division cycle 20 related 1 (Drosophila) 51343 Q9UM11 TAP; MS; IP/WB
Lim HJ , et al. 2013
HCFC1 host cell factor C1 (VP16-accessory protein) 3054 P51610 ChIP; IP/WB
Liu W , et al. 2010
HIST1H3A histone cluster 1, H3a 8350 P68431 IP/WB
Feng W , et al. 2010
HIST1H4A histone cluster 1, H4a 8359 B2R4R0 GST; IP/WB
Qi HH , et al. 2010
HIST3H3 histone cluster 3, H3 8290 Q16695 MS
Bartke T , et al. 2010
MAGEA10 Melanoma-associated antigen 10 4109 P43363 IP; LC-MS/MS
Huttlin EL , et al. 2015
MAML1 mastermind-like 1 (Drosophila) 9794 Q92585 ChIP; IP/WB
Yatim A , et al. 2012
NOTCH1 notch 1 4851 P46531 MS
Yatim A , et al. 2012
PHF8 PHD finger protein 8 23133 Q9UPP1 TAP; MS; IP/WB
Lim HJ , et al. 2013
POLR2A polymerase (RNA) II (DNA directed) polypeptide A, 220kDa 5430 P24928 ChIP; IP/WB
Fortschegger K , et al. 2010
POLR2C polymerase (RNA) II (DNA directed) polypeptide C, 33kDa 5432 P19387 ChIP; IP/WB
Fortschegger K , et al. 2010
RARA retinoic acid receptor, alpha 5914 P10276 FRET
Qiu J , et al. 2010
RBPJ recombination signal binding protein for immunoglobulin kappa J region 3516 Q06330 ChIP; IP/WB
Yatim A , et al. 2012
RPAP1 RNA polymerase II associated protein 1 26015 Q9BWH6 LC-MS/MS
Jeronimo C , et al. 2007
SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae) 7341 P63165 LC-MS/MS
Matafora V , et al. 2009
SUMO2 SMT3 suppressor of mif two 3 homolog 2 (S. cerevisiae) 6613 P61956 MS
Ouyang J , et al. 2009
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010
WDR5 WD repeat domain 5 609012 N/A IP/WB
Feng W , et al. 2010
ZNF711 zinc finger protein 711 7552 Q6PK66 IP/WB
Kleine-Kohlbrecher D , et al. 2010

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