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Intellectual disability

Gene: PPP1R21

Green List (high evidence)

PPP1R21 (protein phosphatase 1 regulatory subunit 21)
EnsemblGeneIds (GRCh38): ENSG00000162869
EnsemblGeneIds (GRCh37): ENSG00000162869
PPP1R21 is in 2 panels

4 reviews

Catherine Snow (Genomics England)

Comment on list classification: Comment on list classification: Gene status was set to Green due to expert reviews by both Konstantinos Varvagiannis and Zornitza Stark on PPP1R21. 9 individuals from 7 unrelated families. All (7 different) variants reported to date are truncating. PPP1R21 is currently not in OMIM or G2P.
Created: 23 May 2019, 11:09 a.m.

Louise Daugherty (Genomics England Curator)

Comment on publications: added publications recommended by external reviews
Created: 15 Jan 2019, 5:27 p.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Bi-allelic LoF variants now reported in 9 individuals from 7 unrelated families with a severe neurodevelopmental phenotype. Functional studies in the most recent paper, 30520571
Created: 10 Dec 2018, 3:07 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
severe intellectual disability, hypotonia

Publications

Variants in this GENE are reported as part of current diagnostic practice

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in PPP1R21 have been reported so far in 9 individuals from 7 unrelated families. All (7 different) variants reported to date are truncating.

PMID: 29808498 is the first detailed clinical description on the related phenotype. 3 individuals from 3 families are reported. One of these individuals was previously included in a larger patient cohort (in PMID: 28940097).

In a subsequent further publication, Rehman et al. (https://doi.org/10.1002/humu.23694) describe 6 additional patients from 4 unrelated consanguineous families. Again, these individuals were homozygous for truncating mutations. The authors summarize the findings in their patients as well as the previously reported ones.

Common features included feeding difficulties, hypotonia with severe global DD and mildly coarsened facial features (all were observed in 9/9), visual anomalies (8/9), respiratory problems (7/9), cardiac anomalies (4/9) and hepato-/splenomegaly (3/7). Brain MRI anomalies were observed in the majority. DD was severe in all and ID (which is not explicitly mentioned) was evident from the clinical description of several individuals (eg. in PMID: 29808498).

In total 7 loss-of-function variants have been reported. The authors in the first article underscore the possibility of less severe phenotypes associated to biallelic missense variants (although none has been reported so far).

Functional studies have shown great reduction (but not complete absence) of PPP1R21 mRNA levels in patient fibroblasts compared to controls. A role of PPP1R21 in the endosomal-lysosomal function is demonstrated in line with the presence of myelin figures in patient fibroblasts as well as some phenotypic similarities to neurometabolic/lysosomal storage disorders.

Most variants reported in the most recent publication except one (NM_001135629.2:c.1607dupT) seem to affect all 3 PPP1R21 isoforms (which also seems to be the case for previously published variants). c.1607dupT appears to be the single truncating variant affecting 2 (of 3) isoforms. This variant was however shown to have severely reduced expression in fibroblasts upon qPCR, absent protein staining, and increase in myelin figures.

Ppp1r21 is expressed in embryonic mouse cortex.

Overall, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Created: 7 Dec 2018, 1:20 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Generalized hypotonia; Feeding difficulties; Profound global developmental delay; Abnormality of the face; Abnormality of vision; Abnormal heart morphology; Abnormality of the respiratory system; Hepatosplenomegaly

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review
Phenotypes
  • Hepatosplenomegaly
  • Abnormality of the respiratory system
  • Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology
Clinvar variants
Variants in PPP1R21
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

29 Jul 2019, Gel status: 3

Set Phenotypes

Catherine Snow (Genomics England)

Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system to Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology

29 Jul 2019, Gel status: 3

Set Phenotypes

Catherine Snow (Genomics England)

Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system, Hepatosplenomegaly; Profound global developmental delay; Abnormal heart morphology; Generalized hypotonia; Feeding difficulties; Abnormality of the face; Abnormality of vision to Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to PPP1R21. Source Expert Review was added to PPP1R21. Added phenotypes Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology, Abnormality of the respiratory system, Hepatosplenomegaly for gene: PPP1R21 Rating Changed from No List (delete) to Green List (high evidence)

15 Jan 2019, Gel status: 0

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: PPP1R21 were set to 29808498; 28940097

7 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: PPP1R21 was added gene: PPP1R21 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PPP1R21 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP1R21 were set to 29808498; 28940097 Phenotypes for gene: PPP1R21 were set to Generalized hypotonia; Feeding difficulties; Profound global developmental delay; Abnormality of the face; Abnormality of vision; Abnormal heart morphology; Abnormality of the respiratory system; Hepatosplenomegaly Penetrance for gene: PPP1R21 were set to Complete Review for gene: PPP1R21 was set to GREEN