Human Gene Module / Chromosome 19 / PIK3R2

PIK3R2phosphoinositide-3-kinase regulatory subunit 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 11
Rare Variants / Common Variants
12 / 0
Aliases
PIK3R2, MPPH,  P85B,  p85,  p85-BETA
Associated Syndromes
-
Chromosome Band
19p13.11
Associated Disorders
DD/NDD, ASD, EPS
Relevance to Autism

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Molecular Function

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to PIK3R2 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes Rivire JB , et al. (2012) No DD, epilepsy, ASD
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly Negishi Y , et al. (2017) No -
4 Support Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability Reijnders MRF , et al. (2017) No Macrocephaly
5 Support - Hiraide T et al. (2021) No -
6 Support - Mahjani B et al. (2021) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Yuan B et al. (2023) Yes -
9 Support - Wang J et al. (2023) Yes -
10 Support - Sanchis-Juan A et al. (2023) No -
11 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1737-1G>A - splice_site_variant De novo - - 36881370 Yuan B et al. (2023)
c.988T>G p.Trp330Gly missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.356C>T p.Ser119Phe missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.49C>T p.Arg17Trp missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1117G>A p.Gly373Arg missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.1117G>A p.Gly373Arg missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1192G>A p.Val398Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1117G>A p.Gly373Arg missense_variant De novo - Simplex 28086757 Negishi Y , et al. (2017)
c.1117G>A p.Gly373Arg missense_variant De novo - Multiplex 22729224 Rivire JB , et al. (2012)
c.1674G>C p.Lys558Asn missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1493_1494del p.Gln498ArgfsTer14 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1117G>A p.Gly373Arg missense_variant De novo in 7 families, unknown in 3 families - Unknown 22729224 Rivire JB , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
S
icon
S

Score remained at S

Description

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2017
S
icon
S

Score remained at S

Description

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Reports Added
[Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.2017]
1/1/2017
S
icon
S

Score remained at S

Description

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Reports Added
[A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly.2017]
1/1/2016
S
icon
S

Score remained at S

Description

Exome sequencing of families with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) identified a recurrent missense variant in the PIK3R2 gene in 11 unrelated families; in one of these families, an affected male sibling was also diagnosed with Asperger syndrome, while one of two affected female siblings also had Asperger-like features (Riviere et al., 2012).

Reports Added
[De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014]
Krishnan Probability Score

Score 0.4914923103164

Ranking 5501/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.93962688446496

Ranking 2837/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.58019983182577

Ranking 647/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 4

Ranking 319/461 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.
Original Source
Zhang D Score

Score 0.40530292918526

Ranking 1397/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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