Human Gene Module / Chromosome 1 / POGZ

POGZPogo transposable element with ZNF domain

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
12 / 21
Rare Variants / Common Variants
73 / 0
Aliases
POGZ, RP11-806J18.2,  KIAA0461,  MGC71543,  SUHW5,  ZNF280E,  ZNF635,  ZNF635m
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
1q21.3
Associated Disorders
DD/NDD, EPS, ASD
Relevance to Autism

De novo variants in the POGZ gene was been identified in autistic probands in two separate reports (Neale et al., 2012; Iossifov et al., 2012).

Molecular Function

The protein encoded by this gene appears to be a zinc finger protein containing a transposase domain at the C-terminus. This protein was found to interact with the transcription factor SP1 in a yeast two-hybrid system. Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion. Probably through its association with CBX5 plays a role in mitotic chromosome segregation by regulating aurora kinase B/AURKB activation and AURKB and CBX5 dissociation from chromosome arms.

Reports related to POGZ (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
4 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
5 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No Epilpesy/seizures
7 Support A case of autism spectrum disorder arising from a de novo missense mutation in POGZ. Fukai R , et al. (2015) Yes -
8 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
9 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
10 Support Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. Hashimoto R , et al. (2015) Yes -
11 Recent recommendation POGZ truncating alleles cause syndromic intellectual disability. White J , et al. (2016) No ASD
12 Support A novel de novo POGZ mutation in a patient with intellectual disability. Tan B , et al. (2016) No -
13 Recent recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Homsy J , et al. (2016) No NDD (DD, learning disabilities) in 1/2 cases
14 Recent recommendation Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders. Stessman HA , et al. (2016) No ASD
15 Support De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. Matsumura K , et al. (2016) No -
16 Support De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly. Ye Y , et al. (2016) No ASD (1 case)
17 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
18 Support Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics. Loviglio MN , et al. (2016) No Behavioral abnormalities (self-injurious, stereoty
19 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
20 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
21 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
Rare Variants   (73)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2459_2462dupGTAC p.Phe822TyrfsTer43 frameshift_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.3600_3607dupTGATGACG p.Glu1203ValfsTer28 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
c.3085C>T p.His1029Tyr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.406C>T p.Pro189Ser missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.398C>G p.Thr133Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.407A>G p.Asn136Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3140G>A p.Arg1047Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
AC/A - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1075C>T p.Arg359Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
del(AG) - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
del(T) - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.329T>G p.Val110Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1610A>G p.Asn537Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1295A>G p.Arg432Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.851G>A p.Arg284Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3014G>A p.Arg1005His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3022C>T p.Arg1008Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1790A>G p.Tyr597Cys missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3354delC p.Leu1119CysfsTer3 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2711T>A p.Leu904Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.3118G>A p.Glu1040Lys missense_variant De novo - Simplex 25694107 Fukai R , et al. (2015)
c.941G>A p.Ser314Asn missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3125A>G p.Gln1042Arg missense_variant De novo - Simplex 26582266 Hashimoto R , et al. (2015)
c.2321_2324delCTCT p.Ser774CysfsTer16 frameshift_variant Unknown Not maternal - 26739615 White J , et al. (2016)
c.2763dupC p.Thr922HisfsTer22 frameshift_variant De novo - - 26739615 White J , et al. (2016)
c.833C>G p.Ser278Ter stop_gained De novo - - 26739615 White J , et al. (2016)
c.2935C>T p.Arg979Ter stop_gained De novo - - 26739615 White J , et al. (2016)
c.2780dupT p.Leu927PhefsTer17 frameshift_variant De novo - - 26739615 White J , et al. (2016)
c.1277_1278insC - frameshift_variant De novo - Simplex 26763879 Tan B , et al. (2016)
c.284-1G>T - splice_site_variant De novo - - 26785492 Homsy J , et al. (2016)
c.2590C>T p.Arg864Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.3001C>T p.Arg1001Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.3456_3457del p.Glu1154ThrfsTer4 frameshift_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.2263del p.Glu755SerfsTer36 frameshift_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.1152dup p.Arg385SerfsTer4 frameshift_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.2432+1G>A p.? splice_site_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.2020del p.Arg674ValfsTer9 frameshift_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.3847C>T p.Gln1283Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.3456_3457del p.Glu1154ThrfsTer4 frameshift_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.3040C>T p.Gln1014Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.2545+1del p? splice_site_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2400dup p.Lys801GlnfsTer7 frameshift_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2836del p.Asp946MetfsTer12 frameshift_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2574del p.His858GlnfsTer13 frameshift_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.1810G>T p.Glu604Ter stop_gained De novo - Multiplex 26942287 Stessman HA , et al. (2016)
c.3001C>T p.Arg1001Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.2196_2198delAG p.Val733del inframe_deletion De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2020del p.Arg674ValfsTer9 frameshift_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.1212C>A p.Tyr404Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.538C>T p.Gln180Ter stop_gained De novo - - 26942287 Stessman HA , et al. (2016)
c.3139G>T p.Glu1047Ter stop_gained De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2291del p.Pro764LeufsTer27 frameshift_variant De novo - Simplex 26942287 Stessman HA , et al. (2016)
c.2501del p.Leu834TrpfsTer20 frameshift_variant Unknown - Multi-generational 26942287 Stessman HA , et al. (2016)
c.2396G>A p.Ser799Asn missense_variant De novo - - 26942287 Stessman HA , et al. (2016)
c.2094_2097dupAACT p.Val700AsnfsTer7 frameshift_variant De novo - - 27148570 Ye Y , et al. (2016)
c.3031C>T p.Gln1011Ter stop_gained De novo - - 27148570 Ye Y , et al. (2016)
c.2750dupC p.Pro918ThrfsTer26 frameshift_variant De novo - - 27148570 Ye Y , et al. (2016)
c.3041delA p.Gln1014ArgfsTer5 frameshift_variant De novo - - 27148570 Ye Y , et al. (2016)
c.2195_2196delCT p.Pro732ArgfsTer11 frameshift_variant Unknown - - 27148570 Ye Y , et al. (2016)
- - copy_number_loss De novo - - 27148570 Ye Y , et al. (2016)
c.2514dupC p.Ser839LeufsTer25 frameshift_variant De novo - - 27148570 Ye Y , et al. (2016)
c.2020del p.Arg674fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
delAGAG - frameshift_variant Unknown Not maternal - 27799067 Loviglio MN , et al. (2016)
c.538C>T p.Gln127Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.2369G>A p.Ser746Asn missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.2369G>A p.Ser746Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1348G>A p.Asp406Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2131_2132delCCinsC p.Pro711LeufsTer27 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1053C>A p.Tyr351Ter stop_gained De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.2980G>T p.Glu994Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.C1638C>G;c.1737C>G;c.1764C>G;c.1896C>G;c.1923C>G p.His546Gln;p.His579Gln;.p.His588Gln;p.His632Gln;p.His641Gln missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.1198C>T;c.1297C>T;c.1324C>T;c.1456C>T;c.1483C>T p.Arg400Ter;p.Arg433Ter;p.Arg442Ter;p.Arg486Ter;p.Arg495Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

De novo variants in the POGZ gene have been identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene (PMID 22542183). no controls (many missense have been observed in EVS). A third de novo LoF variant in the POGZ gene was recently identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified POGZ as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in POGZ were identified in PMID 26739615 in individuals with developmental delay/intellectual disability and, in two cases, ASD. A review of clinical information in individuals with POGZ variants in PMID 26739615 identified shared phentoypic features (developmental delay/intellectual disability, hypotonia, behavioral abnormalities, similar facial features) and proposed that POGZ LoF variants were responsible for a form of syndromic ID. Additional LoF variants in POGZ were identified in previously unreported cases with developmental delay/intellectual disability and/or ASD in PMID 26942287. The authors of this report estimated that protein-truncating POGZ variants were significantly enriched in ASD and/or ID individuals in comparison to the general population (p=4.19E-13, odds ratio 35.8), and that the penetrance of POGZ LoF variant was 65.9% given the incidence of ID (5.12%) in the general population.

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.

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."

04-01-2017
1S

Initial score established: 1S

Description

De novo variants in the POGZ gene have been identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene (PMID 22542183). no controls (many missense have been observed in EVS). A third de novo LoF variant in the POGZ gene was recently identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified POGZ as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in POGZ were identified in PMID 26739615 in individuals with developmental delay/intellectual disability and, in two cases, ASD. A review of clinical information in individuals with POGZ variants in PMID 26739615 identified shared phentoypic features (developmental delay/intellectual disability, hypotonia, behavioral abnormalities, similar facial features) and proposed that POGZ LoF variants were responsible for a form of syndromic ID. Additional LoF variants in POGZ were identified in previously unreported cases with developmental delay/intellectual disability and/or ASD in PMID 26942287. The authors of this report estimated that protein-truncating POGZ variants were significantly enriched in ASD and/or ID individuals in comparison to the general population (p=4.19E-13, odds ratio 35.8), and that the penetrance of POGZ LoF variant was 65.9% given the incidence of ID (5.12%) in the general population.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.2015] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [A novel de novo POGZ mutation in a patient with intellectual disability.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [POGZ truncating alleles cause syndromic intellectual disability.2016] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.2016] [De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly.2016] [De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [De novo gene disruptions in children on the autistic spectrum.2012] [Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder.2015] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Excess of rare, inherited truncating mutations in autism.2015] [Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.2016] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
CNVs associated with POGZ(1 CNVs)
1q21.3 17 Deletion-Duplication 27  /  86
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
TMEM171 Transmembrane protein 171 Human Protein Binding 134285 Q8WVE6
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