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
3 / 8
Rare Variants / Common Variants
26 / 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.

Reports related to PPP2R5D (8 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 (5/7 cases)
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
Rare Variants   (26)
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)
Common Variants  

No common variants reported.

SFARI Gene score
4S

Minimal Evidence, Syndromic

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.

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.

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

04-01-2017
4S

Initial score established: 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.

CNVs associated with PPP2R5D(1 CNVs)
6p21.1 11 Deletion-Duplication 18  /  30
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