Human Gene Module / Chromosome 6 / PPP2R5D

PPP2R5DProtein phosphatase 2, regulatory subunit B', delta

Score
4S
Minimal Evidence, Syndromic Criteria 4.1, Syndromic
Autism Reports / Total Reports
5 / 13
Rare Variants / Common Variants
36 / 0
Aliases
PPP2R5D, B56D,  MRD35
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
6p21.1
Associated Disorders
ID, ASD
Relevance to Autism

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies.

Molecular Function

This gene encodes a delta isoform of the regulatory subunit B56 subfamily and belongs to the phosphatase 2A regulatory subunit B family, which might modulate substrate selectivity and catalytic activity of protein phosphatase 2A, which is one of the four major Ser/Thr phosphatases and has been implicated in the negative control of cell growth and division.

External Links
Gene CardEntrez GeneOMIMUniProtHumanBasePubMed
Reports related to PPP2R5D (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
3 Support Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Loveday C , et al. (2015) No -
4 Recent Recommendation B56-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. Houge G , et al. (2015) No -
5 Primary De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Shang L , et al. (2015) No ASD
6 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No ID, macrocephaly, hypotonia
7 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
8 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes Hypotonia, macrocephaly
9 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
10 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No Macrocephaly
11 Support Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Reijnders MRF , et al. (2017) No Macrocephaly
12 Support Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism. Yeung KS , et al. (2018) No ASD
13 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
661+T 221-! frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1672A>G p.Met558Val missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.602C>G p.Pro201Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 25972378 Loveday C , et al. (2015)
c.598G>A p.Glu200Lys missense_variant De novo - Simplex 25972378 Loveday C , et al. (2015)
c.598G>A p.Glu200Lys missense_variant Unknown - Simplex 25972378 Loveday C , et al. (2015)
c.157C>T p.Pro53Ser missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.598G>A p.Glu200Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.598G>A p.Glu200Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.619T>A p.Trp207Arg missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.598G>A p.Glu200Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.1258G>A p.Glu420Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.1258G>A p.Glu420Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.1258G>A p.Glu420Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.589G>A p.Glu197Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
AAGAG>AAG - frameshift_variant De novo (mosaic) - Simplex 28263302 C Yuen RK , et al. (2017)
c.592G>A p.Glu198Lys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.545C>T p.Thr182Met missense_variant Familial Paternal - 28628100 Geisheker MR , et al. (2017)
c.656G>A p.Arg219His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.592G>A p.Glu198Lys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.274G>A p.Glu92Lys missense_variant De novo - Simplex 28940097 Anazi S , et al. (2017)
c.1258G>A p.Glu420Lys missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.598G>A p.Glu200Lys missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.592G>A p.Glu198Lys missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.592G>A p.Glu198Lys missense_variant De novo - - 29296277 Yeung KS , et al. (2018)
c.592G>A p.Glu198Lys missense_variant De novo - - 29296277 Yeung KS , et al. (2018)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
4S

Minimal Evidence, Syndromic

4S

Score Delta: Score remained at 4.5 + S

criteria met
See SFARI Gene'scoring criteria
4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

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."

4/1/2018
4S
icon
4.5 + S

Score remained at 4.5 + S

Description

4S

Reports Added
[Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism.2018] [Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.2018]
7/1/2017
4S
icon
4S

Score remained at 4S

Description

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies. De novo variants in the PPP2R5D gene (one frameshift, one benign missense) have been identified in SSC probands (Iossifov et al., 2015), although no additional phenotypic information for these probands is available.

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
4/1/2017
4S
icon
4S

Score remained at 4S

Description

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies. De novo variants in the PPP2R5D gene (one frameshift, one benign missense) have been identified in SSC probands (Iossifov et al., 2015), although no additional phenotypic information for these probands is available.

Reports Added
[Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth.2015] [B56-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017]
10/1/2016
4S
icon
4S

Score remained at 4S

Description

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies. De novo variants in the PPP2R5D gene (one frameshift, one benign missense) have been identified in SSC probands (Iossifov et al., 2015), although no additional phenotypic information for these probands is available.

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
1/1/2016
S
icon
4S

Increased from S to 4S

Description

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies. De novo variants in the PPP2R5D gene (one frameshift, one benign missense) have been identified in SSC probands (Iossifov et al., 2015), although no additional phenotypic information for these probands is available.

Krishnan Probability Score

Score 0.49218662672243

Ranking 4686/25841 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 0.99752007894892

Ranking 1313/18225 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 0.46080103163505

Ranking 371/18665 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
Zhang D Score

Score 0.47404963897159

Ranking 713/20870 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
CNVs associated with PPP2R5D(1 CNVs)
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6p21.1 12 Deletion-Duplication 20  /  32
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