Human Gene Module / Chromosome 11 / PHF21A

PHF21APHD finger protein 21A

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
3 / 9
Rare Variants / Common Variants
16 / 0
Aliases
PHF21A, BHC80,  BM-006
Associated Syndromes
Potocki-Shaffer syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11p11.2
Associated Disorders
EP, ADHD, EPS, ASD
Relevance to Autism

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.

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.

Reports related to PHF21A (9 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 includ... 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 -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 22770980 Kim HG , et al. (2012)
- - translocation De novo NA Simplex 22770980 Kim HG , et al. (2012)
c.1738C>T p.His580Tyr stop_gained De novo NA - 31649809 Kim HG , et al. (2019)
c.1285G>A p.Gly429Ser missense_variant De novo NA - 31649809 Kim HG , et al. (2019)
c.1876C>T p.His626Tyr stop_gained De novo NA Simplex 31649809 Kim HG , et al. (2019)
c.1738C>T p.His580Tyr stop_gained De novo NA Simplex 30487643 Hamanaka K , et al. (2018)
c.1471del p.Cys491AlafsTer11 frameshift_variant De novo NA - 31649809 Kim HG , et al. (2019)
c.1538del p.Asp513AlafsTer3 frameshift_variant De novo NA Simplex 31649809 Kim HG , et al. (2019)
c.1471del p.Cys491AlafsTer11 frameshift_variant De novo NA Simplex 31649809 Kim HG , et al. (2019)
c.844dup p.His282ProfsTer43 frameshift_variant Unknown Not maternal - 31649809 Kim HG , et al. (2019)
c.599dup p.Asn200LysfsTer24 frameshift_variant De novo NA Simplex 30487643 Hamanaka K , et al. (2018)
c.1154del p.Ser385ThrfsTer30 frameshift_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.32_33dup p.Val12LysfsTer14 frameshift_variant De novo NA Simplex 30487643 Hamanaka K , et al. (2018)
c.1956del p.Ala653ProfsTer103 frameshift_variant De novo NA Simplex 27479843 Lelieveld SH , et al. (2016)
c.840del p.Ile281SerfsTer14 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
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
1

High Confidence

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,

Score Delta: Score remained at 4S

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.

1/1/2020
4S
icon
4S

Score remained at 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. 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,

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,

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.

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.
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
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
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).
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.
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