Human Gene Module / Chromosome 6 / PPP2R5D

PPP2R5DProtein phosphatase 2, regulatory subunit B', delta

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 37
Rare Variants / Common Variants
71 / 0
EAGLE Score
8.5
Moderate Learn More
Aliases
PPP2R5D, B56D,  MRD35
Associated Syndromes
Hogue-Janssens syndrome 1, Houge-Janssens syndrome 1, DD, Houge-Janssens syndrome 1
Chromosome Band
6p21.1
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
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. Oyama et al., 2022 studied 76 individuals withPPP2R5Dvariants, including 68 with pathogenic de novo variants and four siblings with a novel dominantly inherited pathogenic variant; functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding, or both, while the recurrent p.Glu198Lys missense variant showed the highest C-binding defect and a more severe clinical phenotype and the inherited p.Glu197Gly variant had a mild substrate binding defect. Furthermore, common clinical phenotypes of affected individuals in Oyama et al., 2022 were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%).

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 CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPP2R5D (37 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 -
14 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
15 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
16 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
17 Support - Brunet T et al. (2021) No -
18 Support - Hiraide T et al. (2021) No -
19 Support - Pode-Shakked B et al. (2021) No ASD, epilepsy/seizures
20 Support - Mahjani B et al. (2021) Yes -
21 Support - Álvarez-Mora MI et al. (2022) No -
22 Support - Hu C et al. (2022) Yes -
23 Support - Krgovic D et al. (2022) Yes ID
24 Support - Chen Y et al. (2021) No -
25 Support - Levchenko O et al. (2022) No -
26 Support - Zhou X et al. (2022) Yes -
27 Recent Recommendation - Oyama N et al. (2022) No ASD, DD, ID, epilepsy/seizures
28 Support - Spataro N et al. (2023) No -
29 Support - Smolen KA et al. (2023) No -
30 Support - Karthika Ajit Valaparambil et al. () Yes -
31 Support - Lucie Sedlackova et al. (2024) No ASD
32 Support - Erica Rosina et al. (2024) No -
33 Support - Tamam Khalaf et al. (2024) No ADHD
34 Support - Ruohao Wu et al. (2024) Yes -
35 Support - Axel Schmidt et al. (2024) No -
36 Support - Karen Lob et al. () Yes ADHD, DD
37 Support - Khemika K Sudnawa et al. () No -
Rare Variants   (71)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*76C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.-183C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.-200G>A - missense_variant De novo - - 33004838 Wang T et al. (2020)
c.70-5C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.560C>T p.Ser187Leu missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.92C>T p.Thr31Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.598G>A p.Glu200Lys missense_variant Unknown - - 39136901 Karen Lob et al. ()
c.139G>A p.Glu47Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.145G>A p.Glu49Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.202C>T p.Arg68Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.253G>A p.Asp85Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.263T>C p.Phe88Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.655C>T p.Arg219Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.496G>A p.Ala166Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.523T>C p.Phe175Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1150C>T p.Leu384%3D missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1727C>T p.Pro576Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.139G>A p.Glu47Lys missense_variant De novo - - 26168268 Houge G , et al. (2015)
c.145G>A p.Glu49Lys missense_variant De novo - - 26168268 Houge G , 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.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.589G>A p.Glu197Lys 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.805G>A p.Glu269Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.139G>A p.Glu47Lys missense_variant De novo - - 29296277 Yeung KS , et al. (2018)
c.1258G>A p.Glu420Lys missense_variant De novo - - 26576547 Shang L , et al. (2015)
c.598G>A p.Glu200Lys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.592G>A p.Glu198Lys missense_variant De novo - - 35813072 Krgovic D et al. (2022)
c.758G>A p.Arg253Gln missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.139G>A p.Glu47Lys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.751G>T p.Asp251Tyr missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.752A>C p.Asp251Ala missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.592G>A p.Glu198Lys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.619T>C p.Trp207Arg missense_variant De novo - Simplex 35873028 Chen Y et al. (2021)
c.592G>A p.Glu198Lys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.656G>A p.Arg219His 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.592G>A p.Glu198Lys 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 - - 31036916 Lecoquierre F , et al. (2019)
c.592G>A p.Glu198Lys missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1258G>A p.Glu420Lys missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.307C>T p.His103Tyr missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.625C>T p.His209Tyr missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.139G>A p.Glu47Lys missense_variant De novo - Simplex 25972378 Loveday C , et al. (2015)
c.145G>A p.Glu49Lys missense_variant Unknown - Simplex 25972378 Loveday C , et al. (2015)
c.619T>C p.Trp207Arg missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.139_140delinsAG p.Glu47Arg missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.598G>A p.Glu200Lys missense_variant De novo - Simplex 25972378 Loveday C , et al. (2015)
c.225_226del p.Gly77AlafsTer21 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1672A>G p.Met558Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.598G>A p.Glu200Lys missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.139G>A p.Glu47Lys missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.1258G>A p.Glu420Lys missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.496G>A p.Ala166Thr missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.619T>A p.Trp207Arg missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.545C>T p.Thr182Met missense_variant Familial Paternal - 28628100 Geisheker MR , et al. (2017)
c.751G>C p.Asp251His missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.210del p.Glu71SerfsTer9 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.592G>A p.Glu198Lys missense_variant De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.1645_1646del p.Arg549AspfsTer5 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1267_1270del p.Leu423IlefsTer9 frameshift_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
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)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

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
1
icon
1

Score remained at 1

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
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

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
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

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
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
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
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S 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.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019]
10/1/2017
4S
icon
4S

Decreased from 4S 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.

Reports Added
[Expanding the genetic heterogeneity of intellectual disability.2017] [Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.2017]
7/1/2017
4S
icon
4S

Decreased from 4S 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.

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

Decreased from 4S 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.

Reports Added
[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] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
4S
icon
4S

Decreased from 4S 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.

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).
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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.
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