Intellectual disability
Gene: PLEKHG2

PLEKHG2 (pleckstrin homology and RhoGEF domain containing G2)
EnsemblGeneIds (GRCh38): ENSG00000090924
EnsemblGeneIds (GRCh37): ENSG00000090924
OMIM: 611893, Gene2Phenotype
PLEKHG2 is in 1 panel

4 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Created: 24 Feb 2025, 6:15 p.m. | Last Modified: 24 Feb 2025, 6:15 p.m.

Panel Version: 8.97

Three biallelic PLEKHG2 missense variants have been identified in three unrelated families, in individuals who have Leukodystrophy and acquired microcephaly with or without dystonia (OMIM:616763)(PMID: 26539891, 26573021, 34326120). Segregation of the variant and the condition has been demonstrated in two of these families (PMID: 26573021, 34326120) and functional studies show that although PLEKHG2 gene expression is not affected, the resultant variant peptide has a reduced effect (PMID: 26573021, 35203342).
Created: 28 Aug 2024, 5:23 p.m. | Last Modified: 29 Aug 2024, 10:09 a.m.

Panel Version: 7.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 28 Aug 2024, 5:23 p.m.
Last Modified: 29 Aug 2024, 10:09 a.m.
Panel version: 8.97

Hannah Robinson (South West Genomic Laboratory Hub)

I don't know

Reviews to date relate to biallelic inheritance, not monoallelic inheritance as currently tagged with under an Amber rating. Needs amending.
Created: 20 Aug 2024, 10:22 a.m. | Last Modified: 20 Aug 2024, 10:22 a.m.

Panel Version: 7.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 20 Aug 2024, 10:22 a.m.
Last Modified: 20 Aug 2024, 10:22 a.m.
Panel version: 7.11

Catherine Snow (Genomics England)

Comment on list classification: PLEKHG2 was added to the ID panel and rated Amber by Konstantinos Varvagiannis based on two papers.
Edvardson et al. (2016 - PMID: 26573021) reported five children from 2 unrelated consanguineous Palestinian families, all with same variant homozygous missense variant, although it was stated the families were unrelated, this could be a founder effect. For one family samples were not available for parents only the grandmothers.

Karaca et al. (2015 - PMID: 26539891) identified an individual homozygous for a PLEKHG2 missense variant (NM_022835.2:c.1708G>A or p.Gly570Arg) who also had an affected sibling. This was a large study with limited clinical information.

As only two variants in consanguineous families have been reported and sample information not available for all parents, adding gene to "watchlist" and conclude that it should be Amber.
Created: 29 May 2019, 10:43 a.m. | Last Modified: 17 Jul 2019, 2:21 p.m.

Panel Version: 0.201

Created: 29 May 2019, 10:43 a.m.
Last Modified: 17 Jul 2019, 2:21 p.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.101

Konstantinos Varvagiannis (Other)

I don't know

Karaca et al. (2015 - PMID: 26539891) in a study of 128 - mostly consanguineous - families with neurogenetic disorders and brain malformations, identified an individual homozygous for a PLEKHG2 missense variant (NM_022835.2:c.1708G>A or p.Gly570Arg). This individual (BAB4830) had a similarly affected sib. Features included hypotonia, intellectual disability, microcephaly, cerebellar atrophy and nystagmus (description provided in supplement - Table S1). This variant has been submitted in ClinVar as likely pathogenic by the corresponding laboratory (SCV000537940.1).
-------
Edvardson et al. (2016 - PMID: 26573021) reported on 5 individuals from 2 unrelated consanguineous Palestinian families, harboring a missense variant in the homozygous state (NM_022835.2:c.610C>T or p.Arg204Trp - 1/5 was unavailable for testing).
Unaffected relatives were either heterozygous for this variant or homozygous for the reference allele.

Common features included hypotonia (5/5), DD/ID (5/5), postnatal microcephaly (5/5), dystonia (3/5), nystagmus (2/5) or seizures (1/5) [many of these similar to those reported by Karaca et al]. Brain MRI images were consistent with leukodystrophy and prolonged relaxation of dorsal tegmental tracts (similar findings were not commented by Karaca et al).

PLEKHG2 encodes a Rho guanine exchange factor (RhoGEF). RhoGEFs activate RhoGTPases through release of GDP and binding of GTP. Mutations in other RhoGEFs have been associated with neurodevelopmental disorders.

PLEKHG2 activity was shown to be significantly decreased in HEK293A cells transfected with R204W-PLEKHG2 when compared to tranfection with wt. Western blotting suggested that this was not the result of defective expression.

Using lymphoblastoid cell lines from peripheral B lymphocytes from individuals homozygous for R204W and controls, similar levels of expression were shown between the 2 groups (upon Western Blot).

As the authors note, PLEKHG2 is required for Rac- and Cdc42-stimulated actin polymerization in leukocytes (PMID cited: 24001768).

SDF1a-stimulated actin polymerization was studied in patient cells and was shown to be significantly impaired. In line with this actin polymerization was also impaired upon siRNA-mediated downregulation of PLEKHG2 expression in control cells.
-------
A subsequent submission of the Gly570Arg variant in ClinVar (2017 - SCV000609979.1 - same variant as the one reported by Karaca et al) reports this as a VUS.
-------
PLEKHG2 is associated with Leukodystrophy and acquired microcephaly with or without dystonia (616763) in OMIM.
This gene is not associated with any phenotype in G2P.
PLEKHG2 is included in gene panels for ID offered by some diagnostic laboratories.
-------
As a result, this gene could be considered for inclusion in this panel probably as amber (or green if the current evidence is considered to be sufficient).
Sources: Literature
Created: 22 Jan 2019, 9:05 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Leukodystrophy and acquired microcephaly with or without dystonia, 616763

Publications

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

Created: 22 Jan 2019, 9:05 a.m.

Panel version: 2.597

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
NHS GMS
Expert Review
Expert Review

Phenotypes

Leukodystrophy and acquired microcephaly with or without dystonia, OMIM:616763
leukodystrophy and acquired microcephaly with or without dystonia
MONDO:0014766

OMIM

611893

Clinvar variants

Variants in PLEKHG2

Penetrance

unknown

Publications

Panels with this gene

Intellectual disability