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Intellectual disability

Gene: POLR2A

Green List (high evidence)
POLR2A (RNA polymerase II subunit A)
EnsemblGeneIds (GRCh38): ENSG00000181222
EnsemblGeneIds (GRCh37): ENSG00000181222
OMIM: 180660, Gene2Phenotype
POLR2A is in 4 panels

2 reviews

Rebecca Foulger (Genomics England curator)

POLR2A was added to the panel and rated Green by Konstantinos Varvagiannis. As Konstantinos notes, Haijes et al., 2019 (PMID: 31353023) report 16 individuals with heterozygous de novo POLR2A variants located via GeneMatcher.
The cohort included 3 individuals with truncating variants, 3 in-frame deletions and 10 with missense variants. Delayed development was noted in all individuals varying from mild to severe. Severe epilepsy was noted in three individuals. Although POLR2A is not yet associated with a disorder in OMIM or Gene2Phenotype, there are sufficient unrelated cases in PMID:31353023 for inclusion on the panel and therefore on balance, updated rating from Grey to Green.
Created: 15 Aug 2019, 12:58 p.m. | Last Modified: 15 Aug 2019, 12:58 p.m.
Panel Version: 2.1004
Created: 15 Aug 2019, 12:58 p.m.
Last Modified: 15 Aug 2019, 12:58 p.m.
Panel version: 2.1004

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Haijes et al. (2019 - PMID: 31353023) report on 16 individuals with heterozygous de novo POLR2A variants.

DD in all domains was observed in all individuals, ranging from mild to severe (in 8/16 moderate or more severe). The developmental scores were stable over time (as for eventual catch-up/decline) supporting relevance to the current panel.

POLR2A encodes RPB1, the largest subunit of RNA polymerase II (pol II). Pol II is responsible for the transcription of all protein coding genes as well as several long/short non-coding RNA genes.

Missense, in-frame deletions as well as truncating mutations were observed. POLR2A has a pLI of 1 and a Z-score for missense variants of 7.13 (one of the highest ones). The reported variants did not cluster in specific domains of the protein although many were in regions relatively depleted in benign variants in gnomAD (stretches of desert Z-scores). Measures such as the CADD scores did not discriminate between deleterious ones and those in gnomAD.

Different layers of structural analyses, functional analyses (impaired growth in S. cerevisiae in genetic background lacking transcr. factors Dst1 / Sub1 - suggesting reduced transcriptional fidelity / reduced HeLa cell viability) or phenotypic overlap were used to classify variants in probably disease causing (11), possibly disease causing (4 - only based on phenotypic overlap) or of unknown effect (1 variant - due to unavailable/incomplete phenotype).

Some variants were predicted to act by haploinsufficiency while others (missense ones) by a dominant-negative mechanism, the latter being more likely to result in severe phenotypes.

Mutations in genes encoding subunits of pol III (responsible for tRNA synthesis) are associated with leukodystrophy phenotypes with some limited overlap with POLR2A (delayed myelination/white-matter loss/tooth misalignment). Mutations in genes encoding other subunits of pol II (other than RPB1 encoded by POLR2A) have not been implicated in disease though.

POLR2A is not associated with any phenotype in OMIM/G2P. This gene is included in panels for ID offered by some diagnostic laboratories [eg. Utrecht UMC - affiliation of many co-authors of this study or GeneDx].

As a result, this gene can be considered for inclusion in the ID panel probably as green, or amber.
Sources: Literature
Created: 8 Aug 2019, 11:08 a.m.

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

Phenotypes
Generalized hypotonia; Global developmental delay; Feeding difficulties

Publications

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

Created: 8 Aug 2019, 11:08 a.m.

Panel version: 2.996

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603
  • Global developmental delay
  • Generalized hypotonia
  • Feeding difficulties
OMIM
180660
Clinvar variants
Variants in POLR2A
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

11 May 2020, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: POLR2A were changed from Global developmental delay; Generalized hypotonia; Feeding difficulties to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603; Global developmental delay; Generalized hypotonia; Feeding difficulties

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: polr2a has been classified as Green List (High Evidence).

15 Aug 2019, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: POLR2A were changed from Generalized hypotonia; Global developmental delay; Feeding difficulties to Global developmental delay; Generalized hypotonia; Feeding difficulties

8 Aug 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: POLR2A was added gene: POLR2A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POLR2A were set to 31353023 Phenotypes for gene: POLR2A were set to Generalized hypotonia; Global developmental delay; Feeding difficulties Penetrance for gene: POLR2A were set to unknown Review for gene: POLR2A was set to GREEN gene: POLR2A was marked as current diagnostic