Human Gene Module / Chromosome 11 / PHF21A

PHF21APHD finger protein 21A

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 17
Rare Variants / Common Variants
28 / 0
EAGLE Score
5.35
Limited Learn More
Aliases
PHF21A, BHC80,  BM-006
Associated Syndromes
Potocki-Shaffer syndrome
Chromosome Band
11p11.2
Associated Disorders
ADHD, EP, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (Iossifov et al., 2014; Satterstrom et al., 2020) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals. Three additional de novo likely gene-disruptive variants in PHF21A were identified in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in the same report identified PHF21A as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) in non-neuronal cells.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PHF21A (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Potocki-Shaffer syndrome: comprehensive clinical assessment, review of the literature, and proposals for medical management Swarr DT , et al. (2010) No ASD
2 Support Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies Kim HG , et al. (2012) No -
3 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
5 Support De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies Hamanaka K , et al. (2018) No Epilepsy/seizures, autistic features
6 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Recent Recommendation Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism Kim HG , et al. (2019) No ASD, ADHD
9 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
10 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
11 Support - Bertoli-Avella AM et al. (2021) No -
12 Support - Mahjani B et al. (2021) Yes -
13 Recent Recommendation - Zhou X et al. (2022) Yes -
14 Support - Chan AJS et al. (2022) Yes -
15 Support - Poole RL et al. (2023) No DD, autistic behavior
16 Support - et al. () No -
17 Support - et al. () No -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 22770980 Kim HG , et al. (2012)
- - insertion Familial Paternal - 36309498 Chan AJS et al. (2022)
- - translocation De novo - Simplex 22770980 Kim HG , et al. (2012)
c.153+1G>C - splice_site_variant De novo - Simplex 38264805 et al. ()
c.1168C>T p.Arg390Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1738C>T p.His580Tyr stop_gained De novo - - 31649809 Kim HG , et al. (2019)
c.649_650del p.Pro217ThrfsTer7 frameshift_variant De novo - - 38256219 et al. ()
c.1285G>A p.Gly429Ser missense_variant De novo - - 31649809 Kim HG , et al. (2019)
c.1876C>T p.His626Tyr stop_gained De novo - Simplex 31649809 Kim HG , et al. (2019)
c.706C>T p.Arg236Ter stop_gained De novo - Simplex 36876344 Poole RL et al. (2023)
c.1229G>C p.Arg410Pro missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1738C>T p.Arg580Ter stop_gained De novo - Simplex 32530565 Suzuki T et al. (2020)
c.1741C>T p.Arg581Ter stop_gained Unknown - Simplex 36876344 Poole RL et al. (2023)
c.1738C>T p.His580Tyr stop_gained De novo - Simplex 30487643 Hamanaka K , et al. (2018)
c.1955del p.Pro652LeufsTer104 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1143del p.Glu382LysfsTer33 splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1471del p.Cys491AlafsTer11 frameshift_variant De novo - - 31649809 Kim HG , et al. (2019)
c.1538del p.Asp513AlafsTer3 frameshift_variant De novo - Simplex 31649809 Kim HG , et al. (2019)
c.1471del p.Cys491AlafsTer11 frameshift_variant De novo - Simplex 31649809 Kim HG , et al. (2019)
c.1154del p.Ser385ThrfsTer30 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.599dup p.Asn200LysfsTer24 frameshift_variant De novo - Simplex 30487643 Hamanaka K , et al. (2018)
c.844dup p.His282ProfsTer43 frameshift_variant Unknown Not maternal - 31649809 Kim HG , et al. (2019)
c.32_33dup p.Val12LysfsTer14 frameshift_variant De novo - Simplex 30487643 Hamanaka K , et al. (2018)
c.1956del p.Ala653ProfsTer103 frameshift_variant De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.840del p.Ile281SerfsTer14 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.959_967delinsTTACA p.Gln320LeufsTer53 frameshift_variant De novo - Simplex 36876344 Poole RL et al. (2023)
c.973_976del p.Lys325GlnfsTer47 frameshift_variant De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.-83-1G>A - splice_site_variant Familial Paternal Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

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."

4/1/2021
1
icon
1

Score remained at 1

Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals. Kim et al., 2019 identified seven previously unreported individuals with PHF21A variants presenting with a form of syndromic intellectual disability characterized by developmental delay, behavioral abnormalities (including autism spectrum disorder, ADHD, and anxiety), seizures/epilepsy, hypotonia, digital abnormalities (including tapered fingers, clinodactyly, and syndactyly), dysmorphic features, and obesity,

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
7/1/2020
1
icon
1

Score remained at 1

Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals. Kim et al., 2019 identified seven previously unreported individuals with PHF21A variants presenting with a form of syndromic intellectual disability characterized by developmental delay, behavioral abnormalities (including autism spectrum disorder, ADHD, and anxiety), seizures/epilepsy, hypotonia, digital abnormalities (including tapered fingers, clinodactyly, and syndactyly), dysmorphic features, and obesity,

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

Score remained at 1

Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals. Kim et al., 2019 identified seven previously unreported individuals with PHF21A variants presenting with a form of syndromic intellectual disability characterized by developmental delay, behavioral abnormalities (including autism spectrum disorder, ADHD, and anxiety), seizures/epilepsy, hypotonia, digital abnormalities (including tapered fingers, clinodactyly, and syndactyly), dysmorphic features, and obesity,

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals. Kim et al., 2019 identified seven previously unreported individuals with PHF21A variants presenting with a form of syndromic intellectual disability characterized by developmental delay, behavioral abnormalities (including autism spectrum disorder, ADHD, and anxiety), seizures/epilepsy, hypotonia, digital abnormalities (including tapered fingers, clinodactyly, and syndactyly), dysmorphic features, and obesity,

Reports Added
[Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems includ...2019] [New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
icon
4S

Increased from to 4S

Description

De novo likely-gene disruptive (LGD) variants in the PHF21A gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and in a proband with intellectual disability (Lelieveld et al., 2016). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PHF21A as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) (Coe et al., 2018). De novo translocations disrupting the PHF21A gene, as well as de novo truncating variants in PHF21A, have been identified in patients presenting with intellectual disability and dysmorphic facial features (Kim et al., 2012; Hamanaka et al., 2018). Potocki-Shaffer syndrome (OMIM 601224) is a contiguous gene deletion syndrome characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina; autistic behavior has also been reported to associate with this syndrome (Swarr et al., 2010). Potocki-Shaffer syndrome involves genes on chromosome 11p11.2, and PHF21A has been proposed as a candidate gene responsible for at least some of the phenotypes observed in affected individuals.

Krishnan Probability Score

Score 0.49533318659725

Ranking 3042/25841 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 0.99967548610074

Ranking 854/18225 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
Iossifov Probability Score

Score 0.861

Ranking 182/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.48492122264332

Ranking 417/18665 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
Zhang D Score

Score 0.075803420341275

Ranking 6631/20870 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
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