Human Gene Module / Chromosome X / PHF8

PHF8PHD finger protein 8

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
35 / 0
Aliases
PHF8, RP13-444K19.2,  JHDM1F,  MRXSSD,  ZNF422
Associated Syndromes
-
Chromosome Band
Xp11.22
Associated Disorders
ID
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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PHF8 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate Laumonnier F , et al. (2005) No -
2 Support A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate Abidi F , et al. (2007) No -
3 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 Koivisto AM , et al. (2007) No -
4 Primary Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE Nava C , et al. (2012) Yes ID
5 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
6 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No Microcephaly
7 Recent Recommendation JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling Riveiro AR , et al. (2017) No -
8 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
9 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
10 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
11 Support - Balan S et al. (2021) Yes -
12 Support - Bruno LP et al. (2021) Yes -
13 Recent Recommendation - Sobering AK et al. (2022) No ASD, ADHD, epilepsy/seizures
14 Support - Isabelle Schrauwen et al. (2024) Yes -
15 Support - Noor Smal et al. () Yes -
Rare Variants   (35)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*1101G>A - missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.529T>A p.Ser177Thr stop_gained De novo - - 17594395 Abidi F , et al. (2007)
c.264C>A p.Asn88Lys missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.1627-1G>A - splice_site_variant De novo - - 35469323 Sobering AK et al. (2022)
c.*1112G>C - missense_variant Familial Maternal - 34262135 Balan S et al. (2021)
c.2475G>C p.Glu825Asp missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.704+1G>A - splice_site_variant De novo - Simplex 35469323 Sobering AK et al. (2022)
c.124G>T p.Val42Leu missense_variant Familial Maternal - 34262135 Balan S et al. (2021)
c.1731-2A>G - splice_site_variant Familial Maternal Simplex 38965372 Noor Smal et al. ()
c.2239G>A p.Glu747Lys missense_variant Familial Maternal - 34262135 Balan S et al. (2021)
- - copy_number_loss Familial Maternal Multiplex 38755281 Isabelle Schrauwen et al. (2024)
c.1249+5G>C - splice_site_variant Familial Maternal Simplex 25167861 Redin C , et al. (2014)
- p.Gly316_Arg380del inframe_deletion Familial Maternal - 35469323 Sobering AK et al. (2022)
c.143A>G p.Tyr48Cys missense_variant Familial Maternal - 35469323 Sobering AK et al. (2022)
c.808C>T p.Arg270Cys missense_variant Familial Maternal - 35469323 Sobering AK et al. (2022)
c.2190_2192del p.Leu731del inframe_deletion De novo - Simplex 34948243 Bruno LP et al. (2021)
c.1150G>A p.Glu384Lys missense_variant Familial Maternal - 35469323 Sobering AK et al. (2022)
c.1731-2A>G - splice_site_variant Familial Maternal Simplex 35469323 Sobering AK et al. (2022)
c.252C>A p.Tyr84Ter stop_gained Familial Maternal Simplex 31906484 Ibarluzea N , et al. (2020)
c.862C>T p.Gln288Ter stop_gained Familial Maternal Multiplex 35469323 Sobering AK et al. (2022)
c.2794T>C p.Cys932Arg missense_variant Familial Maternal - 31209962 Aspromonte MC , et al. (2019)
c.2972A>G p.Asn991Ser missense_variant Familial Maternal Simplex 32530565 Suzuki T et al. (2020)
c.846dup p.His283SerfsTer3 frameshift_variant Familial Maternal - 35469323 Sobering AK et al. (2022)
c.257C>T p.Thr86Met missense_variant Familial Maternal Multiplex 35469323 Sobering AK et al. (2022)
c.294-1820_597-603del - inframe_deletion Familial Maternal Simplex 35469323 Sobering AK et al. (2022)
c.2868dup p.Thr957HisfsTer19 frameshift_variant Familial Maternal - 35469323 Sobering AK et al. (2022)
c.836C>T p.Phe279Ser missense_variant Familial Maternal Multiplex 17661819 Koivisto AM , et al. (2007)
c.2904_2906del p.Ser969del inframe_deletion Familial Maternal Multiplex 23092983 Nava C , et al. (2012)
c.1027C>T p.Gln343Ter stop_gained Familial Maternal Extended multiplex 35469323 Sobering AK et al. (2022)
c.631C>T p.Arg211Ter stop_gained Familial Maternal Multi-generational 16199551 Laumonnier F , et al. (2005)
c.2073_2074insTG p.Glu692TrpfsTer174 frameshift_variant De novo - Simplex 35469323 Sobering AK et al. (2022)
c.2104del p.Glu702ArgfsTer163 frameshift_variant Familial Maternal Simplex 35469323 Sobering AK et al. (2022)
del(ACAGGTCTTCCC) - splice_site_variant Familial Maternal Multi-generational 16199551 Laumonnier F , et al. (2005)
c.1731-2A>G - splice_site_variant Familial Maternal Multiplex (monozygotic twins) 35469323 Sobering AK et al. (2022)
c.738dup p.Arg247SerfsTer17 frameshift_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

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).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

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."

7/1/2020
S
icon
S

Score remained at S

Description

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).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
1/1/2020
S
icon
S

Score remained at S

Description

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).

Reports Added
[Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

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).

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

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).

Reports Added
[Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019]
Krishnan Probability Score

Score 0.49502600193412

Ranking 3268/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99823985258815

Ranking 1218/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94235519684495

Ranking 15275/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 5

Ranking 288/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.54398739843134

Ranking 265/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDC26 cell division cycle 26 Human Protein Binding 246184 Q8NHZ8
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