PHF21APHD finger protein 21A
Autism Reports / Total Reports
8 / 18Rare Variants / Common Variants
29 / 0Aliases
PHF21A, BHC80, BM-006Associated Syndromes
Potocki-Shaffer syndromeChromosome Band
11p11.2Associated Disorders
ADHD, EP, ASD, EPSGenetic Category
Rare Single Gene Mutation, SyndromicRelevance 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
SFARI Genomic Platforms
Reports related to PHF21A (18 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 | - | Luigi Vetri et al. (2024) | No | - |
| 17 | Support | - | Duha Hejla et al. (2024) | No | - |
| 18 | Support | - | Yasser Al-Sarraj et al. (2024) | Yes | - |
Rare Variants (29)
| 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.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.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.153+1G>C | - | splice_site_variant | De novo | - | Simplex | 38264805 | Duha Hejla et al. (2024) | |
| 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.649_650del | p.Pro217ThrfsTer7 | frameshift_variant | De novo | - | - | 38256219 | Luigi Vetri et al. (2024) | |
| c.1471del | p.Cys491AlafsTer11 | frameshift_variant | De novo | - | Simplex | 31649809 | Kim HG , et al. (2019) | |
| c.1196C>A | p.Pro399Gln | missense_variant | De novo | - | Unknown | 38572415 | Yasser Al-Sarraj et al. (2024) | |
| 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
High Confidence, Syndromic
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe 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.
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
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,
7/1/2020
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,
1/1/2020
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,
10/1/2019
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
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
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
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ExAC Score
Score 0.99967548610074
Ranking 854/18225 scored genes
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Iossifov Probability Score
Score 0.861
Ranking 182/239 scored genes
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Sanders TADA Score
Score 0.48492122264332
Ranking 417/18665 scored genes
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Zhang D Score
Score 0.075803420341275
Ranking 6631/20870 scored genes
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