Human Gene Module / Chromosome 1 / POGZ

POGZPogo transposable element with ZNF domain

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
21 / 36
Rare Variants / Common Variants
151 / 0
Aliases
POGZ, RP11-806J18.2,  KIAA0461,  MGC71543,  SUHW5,  ZNF280E,  ZNF635,  ZNF635m
Associated Syndromes
White-Sutton syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
1q21.3
Associated Disorders
EPS, ID, DD/NDD, ASD
Relevance to Autism

Recurrent mutations in the POGZ gene have been identified in multiple individuals with ASD as described below. De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 White et al., 2016 in individuals with developmental delay/intellectual disability and, in two cases, ASD (PMID 26739615). Furthermore, a review of clinical information in individuals with POGZ variants in this report 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 intellectual disability. Additional LoF variants in POGZ were identified in previously unreported cases with developmental delay/intellectual disability and/or ASD in Stessman et al., 2016 (PMID 26942287). The authors of this report estimated that protein-truncating POGZ variants were significantly enriched in individuals with ASD and/or intellectual disability 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.

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 (36 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 DD, learning disabilities
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
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 -
22 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
23 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
24 Support Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder Du X , et al. (2018) Yes DD/ID
25 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD
26 Support POGZ-related epilepsy: Case report and review of the literature Ferretti A , et al. (2019) No DD, ID, epilepsy/seizures, autistic features
27 Support Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development Zhao W , et al. (2019) Yes -
28 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
29 Support POGZ de novo missense variants in neuropsychiatric disorders Zhao W , et al. (2019) Yes -
30 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
31 Support Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome) Assia Batzir N , et al. (2019) No ASD or autistic features
32 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
33 Recent recommendation Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes Matsumura K , et al. (2020) Yes -
34 Support A novel patient with White-Sutton syndrome refines the mutational and clinical repertoire of the POGZ-related phenotype and suggests further observations Pascolini G et al. (2020) No ASD
35 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
36 Support - Garde A et al. (2021) No DD, ID/learning disability, stereotypy
Rare Variants   (151)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 27148570 Ye Y , et al. (2016)
c.1447C>T p.Gln483Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1522C>T p.Arg508Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1608C>A p.Tyr536Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3022C>T p.Arg1008Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3424C>T p.Arg1142Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3031C>T p.Gln1011Ter stop_gained De novo NA - 27148570 Ye Y , et al. (2016)
c.2053C>T p.Arg685Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.2080C>T p.Arg694Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.538C>T p.Gln180Ter stop_gained De novo NA - 27824329 Wang T , et al. (2016)
c.2518+1del - splice_site_variant De novo NA - 33277917 Garde A et al. (2021)
c.284-1G>T - splice_site_variant De novo NA - 26785492 Homsy J , et al. (2016)
c.3022C>T p.Arg1008Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.2092C>T p.Arg698Ter stop_gained De novo NA - 33277917 Garde A et al. (2021)
c.2310C>G p.Tyr770Ter stop_gained De novo NA - 33277917 Garde A et al. (2021)
c.2451C>A p.Cys817Ter stop_gained De novo NA - 33277917 Garde A et al. (2021)
c.833C>G p.Ser278Ter stop_gained De novo NA - 26739615 White J , et al. (2016)
c.481C>T p.Arg161Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2935C>T p.Arg979Ter stop_gained De novo NA - 26739615 White J , et al. (2016)
AC>A - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1796C>T p.Ser599Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1958G>A p.Arg653Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3116G>A p.Arg1039His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3694C>T p.Arg1232Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1348G>A p.Val450Ile missense_variant Unknown - - 31196716 Zhao W , et al. (2019)
c.1792C>G p.Arg598Gly missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.538C>T p.Gln180Ter stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.2405+1G>A - splice_site_variant De novo NA - 26942287 Stessman HA , et al. (2016)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
c.2369G>A p.Ser746Asn missense_variant De novo NA - 27824329 Wang T , et al. (2016)
c.1534C>A p.His512Asn missense_variant De novo NA - 31347273 Zhao W , et al. (2019)
c.1496G>T p.Cys499Phe missense_variant De novo NA - 33277917 Garde A et al. (2021)
c.1727T>C p.Leu576Pro missense_variant De novo NA - 33277917 Garde A et al. (2021)
- p.Asn882LysfsTer14 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.3631C>T p.Arg1211Ter stop_gained De novo NA - 32359026 Pascolini G et al. (2020)
c.1212C>A p.Tyr404Ter stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.2708C>T p.Ala903Val stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.2980G>T p.Glu994Ter stop_gained De novo NA - 28191889 Stessman HA , et al. (2017)
c.3118G>A p.Glu1040Lys missense_variant De novo NA - 33277917 Garde A et al. (2021)
c.3914T>G p.Leu1305Arg missense_variant De novo NA - 33277917 Garde A et al. (2021)
c.3040C>T p.Gln1014Ter stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.3119C>T p.Thr1040Ile stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.3847C>T p.Gln1283Ter stop_gained De novo NA - 26942287 Stessman HA , et al. (2016)
c.460-2A>C - splice_site_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.3139G>T p.Glu1047Ter stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.1457G>A p.Arg486Gln stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.3424C>T p.Arg1142Ter stop_gained Unknown - - 31782611 Assia Batzir N , et al. (2019)
c.2433-1G>A - splice_site_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.1483C>T p.Arg495Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.1669G>T p.Glu557Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2350C>T p.Arg784Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2555G>A p.Trp852Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2729C>A p.Ser910Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2951C>T p.Ala984Val stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2989C>T p.Arg997Ter stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.353del p.Gly118AlafsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1664C>T p.Pro555Leu missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.2248C>T p.Arg750Trp missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.3119C>T p.Thr1040Ile stop_gained De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2020del p.Arg674ValfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2396G>A p.Ser799Asn missense_variant De novo NA - 26942287 Stessman HA , et al. (2016)
c.1053C>A p.Thr351= stop_gained De novo NA Simplex 28191889 Stessman HA , et al. (2017)
c.1075C>T p.Arg359Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2518+1dup - frameshift_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.1399C>T p.Arg467Trp missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1610G>A p.Arg537His missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2542C>T p.Arg848Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2171dup p.Leu725SerfsTer19 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2403del p.Lys801AsnfsTer10 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2501del p.Leu834TrpfsTer20 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2763G>T p.Glu921Asp missense_variant De novo NA Simplex 30504930 Guo H , et al. (2018)
c.3022C>T p.Arg1008Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.2711T>G p.Leu904Ter stop_gained De novo NA Simplex 31136090 Ferretti A , et al. (2019)
c.2487dup p.Ser830LeufsTer25 frameshift_variant De novo NA - 27148570 Ye Y , et al. (2016)
c.2723dup p.Pro909ThrfsTer26 frameshift_variant De novo NA - 27148570 Ye Y , et al. (2016)
c.3014del p.Gln1005ArgfsTer5 frameshift_variant De novo NA - 27148570 Ye Y , et al. (2016)
c.2366dup p.Ser790GlufsTer9 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1321G>A p.Val441Ile missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.941G>A p.Ser314Asn missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.566del p.Pro189GlnfsTer21 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.2400dup p.Lys801GlnfsTer7 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.3179_3180del p.Tyr1060Ter frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.3139G>T p.Glu1047Ter stop_gained De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.2469del p.Thr824ProfsTer30 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.2809del p.Asp937MetfsTer12 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.3118G>A p.Glu1040Lys missense_variant De novo NA Simplex 25694107 Fukai R , et al. (2015)
c.329T>G p.Val110Gly 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.1810G>T p.Glu604Ter stop_gained De novo NA Multiplex 26942287 Stessman HA , et al. (2016)
c.2168_2169del p.Pro723ArgfsTer11 frameshift_variant Unknown - - 27148570 Ye Y , et al. (2016)
c.2323_2324del p.Leu775ValfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3312del p.Phe1104LeufsTer18 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.2882dup p.Glu962GlyfsTer24 frameshift_variant De novo NA - 26739615 White J , et al. (2016)
c.2898dup p.Lys967GlufsTer19 frameshift_variant De novo NA - 26739615 White J , et al. (2016)
c.2809del p.Ala937ProfsTer4 frameshift_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.3118G>A p.Glu1040Lys missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.1790A>G p.Tyr597Cys missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1295A>G p.Arg432Gly 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.2195_2196del p.Pro732ArgfsTer11 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3014G>A p.Arg1005His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1153_1154del p.Met385ValfsTer9 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1524-3C>G - splice_region_variant Familial Paternal Multiplex 33277917 Garde A et al. (2021)
c.2492del p.His831ProfsTer14 splice_site_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.1580A>G p.Asp527Gly missense_variant De novo NA Simplex 30842647 Boonsawat P , et al. (2019)
c.1981G>A p.Asp661Asn missense_variant Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.1180_1181del p.Met394ValfsTer9 frameshift_variant De novo NA - 33277917 Garde A et al. (2021)
c.1099dup p.Ile367AsnfsTer6 frameshift_variant De novo NA - 26942287 Stessman HA , et al. (2016)
c.2381del p.Leu794TrpfsTer8 frameshift_variant De novo NA - 26942287 Stessman HA , et al. (2016)
c.2020del p.Arg674ValfsTer9 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.2106del p.Leu703CysfsTer7 frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.3574_3575del p.Asp1192Ter frameshift_variant De novo NA - 26942287 Stessman HA , et al. (2016)
c.3125A>G p.Gln1042Arg missense_variant De novo NA Simplex 26582266 Hashimoto R , et al. (2015)
c.1965del p.Glu655AspfsTer19 frameshift_variant De novo NA - 26942287 Stessman HA , et al. (2016)
c.2068_2069insACTA p.Thr690AsnfsTer8 frameshift_variant De novo NA - 27148570 Ye Y , et al. (2016)
c.3258G>A p.Arg1086= synonymous_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.2967dup p.Pro990SerfsTer28 frameshift_variant Unknown - - 31782611 Assia Batzir N , et al. (2019)
c.2827del p.Thr943ProfsTer6 frameshift_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.2316_2318del p.Cys773del inframe_deletion De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.1124_1125del p.Phe375SerfsTer4 frameshift_variant De novo NA Simplex 30555518 Du X , et al. (2018)
c.3432_3433del p.Glu1145ThrfsTer4 frameshift_variant De novo NA - 31452935 Feliciano P et al. (2019)
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.1479del p.Arg493SerfsTer2 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3159del p.Phe1056LeufsTer17 frameshift_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.1577del p.Cys526PhefsTer45 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3085C>T p.His1029Tyr missense_variant Familial Paternal 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)
c.406C>T p.Pro189Ser missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.1222_1223insC p.Val408AlafsTer11 frameshift_variant De novo NA Simplex 26763879 Tan B , et al. (2016)
c.1965del p.Glu655AspfsTer19 frameshift_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.2410del p.Ile804SerfsTer41 frameshift_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.2692del p.Ala898HisfsTer21 frameshift_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.2955del p.Glu985AspfsTer25 frameshift_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.2664del p.Glu889LysfsTer4 splice_site_variant De novo NA Simplex 26942287 Stessman HA , et al. (2016)
c.1125_1126del p.Phe375LeufsTer4 frameshift_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.3043_3044del p.Ser1015LeufsTer2 frameshift_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.3324_3325del p.Leu1108PhefsTer9 frameshift_variant De novo NA - 31782611 Assia Batzir N , et al. (2019)
c.3710_3711del p.Ser1237Ter frameshift_variant Familial Maternal - 31782611 Assia Batzir N , et al. (2019)
c.3689del p.Cys1230PhefsTer35 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.2439_2442del p.Phe813LeufsTer31 frameshift_variant Unknown Not maternal - 26739615 White J , et al. (2016)
c.2432_2433insGTAC p.Cys811TrpfsTer45 frameshift_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.3573_3574insTGATGACG p.Asp1192Ter frameshift_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.2321_2324del p.Ser774CysfsTer16 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.3456_3457del p.Glu1154ThrfsTer4 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.2711T>A p.Leu904Ter stop_gained De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2296_2299del p.Leu766ValfsTer15 frameshift_variant Unknown Not maternal - 27799067 Loviglio MN , et al. (2016)
c.2619del p.Asn873LysfsTer6 frameshift_variant Unknown - Multi-generational 26942287 Stessman HA , et al. (2016)
c.2369G>A;c.2396G>A p.Ser746Asn;p.Ser799Asn missense_variant Familial Paternal Simplex 27824329 Wang T , et al. (2016)
c.3327del p.Leu1110CysfsTer3 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
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 NA Simplex 28263302 C Yuen RK et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

Score Delta: Score remained at 1S

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.

1/1/2021
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

10/1/2020
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

4/1/2020
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

1/1/2020
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

7/1/2019
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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. Functional analysis of two previously reported inherited missense variants in the POGZ gene that were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort demonstrated that these variants resulted in aberrant subcellular localization in transfected HEK293 cells, as well as a failure to rescue deficits in neurite and dendritic spine development in cultured mouse cortical neurons with Pogz knockdown (Zhao et al., 2019). The authors also observed a significant burden of rare POGZ missense variants in ASD cases compared to controls (P = 4.6E-05, odds ratio 3.96).

4/1/2019
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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.

1/1/2019
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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.

10/1/2018
1S
icon
1S

Score remained at 1S

Description

De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (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) in De Rubeis et al., 2014 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 intellectual disability. 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.

4/1/2017
1S
icon
1S

Score remained at 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
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [POGZ truncating alleles cause syndromic intellectual disability.2016] [A novel de novo POGZ mutation in a patient with intellectual disability.2016] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.2016] [De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ.2016] [De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
1/1/2017
1S
icon
1S

Score remained at 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.

10/1/2016
1S
icon
1S

Score remained at 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.

7/1/2016
1S
icon
1S

Score remained at 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.

4/1/2016
1S
icon
1S

Score remained at 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.

1/1/2016
1
icon
1S

Score remained at 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.

4/1/2015
1
icon
1

Score remained at 1

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).

1/1/2015
1
icon
1

Score remained at 1

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).

10/1/2014
3
icon
1

Decreased from 3 to 1

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).

7/1/2014
No data
icon
3

Increased from No data to 3

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).

4/1/2014
No data
icon
3

Increased from No data to 3

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).

Krishnan Probability Score

Score 0.51637770010842

Ranking 1745/25841 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 0.99999912812546

Ranking 292/18225 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 0.958

Ranking 73/239 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 4.6761079775445E-5

Ranking 11/18665 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).
Larsen Cumulative Evidence Score

Score 64

Ranking 23/461 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.
Zhang D Score

Score 0.43666272912927

Ranking 1066/20870 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.
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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