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Intellectual disability

Gene: PUS3

Green List (high evidence)
PUS3 (pseudouridylate synthase 3)
EnsemblGeneIds (GRCh38): ENSG00000110060
EnsemblGeneIds (GRCh37): ENSG00000110060
OMIM: 616283, Gene2Phenotype
PUS3 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis, initially rated as Amber as only two families. Additional evidence from PMID: 30697592 reports 2 additional individuals with intellectual disability, siblings from non consanguineous parents from Northeast Brazil and Southern Italy.
PUS3 is in OMIM and phenotype is relevant but it is currently not in G2P.
PUS3 will be classified as Green as sufficient (<3) unrelated families.
Created: 30 May 2019, 10:07 a.m. | Last Modified: 24 Jun 2019, 3:42 p.m.
Panel Version: 0.192
Created: 30 May 2019, 10:07 a.m.
Last Modified: 24 Jun 2019, 3:42 p.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.114

Konstantinos Varvagiannis (Other)

I don't know

PMID: 30697592 reports 2 additional individuals with intellectual disability, leukoencephalopathy and adult onset nephropathy. These individuals harbored 2 missense variants in the compound heterozygous state (c.497G>A - p.Arg166Gln and c.1097T>C - p.Leu366Pro - Ref. sequence not mentioned).

As a result amber/green rating could be considered.
Created: 31 Jan 2019, 4:35 p.m.
PUS3 (Pseudouridylate synthase 3) is proposed as a gene related to ID in a recent publication on PUS7.

Biallelic mutations in this gene are associated in OMIM with ?Mental retardation, autosomal recessive 55 (MIM 617051).

PMID: 27055666 reports on 3 sisters from a consanguineous Saudi Arabian family with failure to thrive, DD/ID, microcephaly and some common (coarse) facial features. These individuals were homozygous for a stopgain mutation in the last exon of the gene. Pseudouridylation appeared to be defective (as has also been the case with other genes related to ID, eg. PUS7).

PMID: 30308082 describes 1 individual born to consanguineous Palestinian parents, homozygous for a further LoF variant. Despite the localisation of this variant (again in the last exon of the gene) qPCR analyses were suggestive of degradation of the abnormal transcript possibly by NMD. The phenotype consisted of DD/ID and microcephaly.

In a further publication (http://dx.doi.org/10.7124/bc.0008D6) Gulkovskyi et al. report on 2 siblings with ID, born to non-consanguineous Ukranian parents. Pathogenicity of the variant is disputed. [NM_031307.4:c.212A>G or p.(Tyr71Cys) is found in an apparent homozygous state in the sibs but was only found in their father. De novo occurence in the maternal allele is proposed although the possibility of microdeletion missed by aCGH or other plausible mechanisms are not considered. This variant has maximum pathogenicity scores in silico (not discussed) and has an allele frequency of 0.00006717 in gnomAD and no homozygotes. The authors did not perform studies of pseudouridylation but examined for the presence of hypoproteinemia, observed in some disorders due to disruption of this process).

PUS3 is not associated with any phenotype in G2P but is associated with disease in OMIM.

The gene is included in gene panels for ID offered by various diagnostic laboratories (including Radboudumc). PUS1 is included in the current panel as green and PUS7 has been suggested for inclusion.

As a result, this gene can be considered for inclusion as amber (2 families) or green (given the supportive functional studies and/or the proposed role for the gene).
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 10 Dec 2018, 11:49 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Mental retardation, autosomal recessive 55 (MIM 617051)

Publications

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

Created: 10 Dec 2018, 11:49 a.m.

Panel version: 2.621

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review
Phenotypes
  • Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
OMIM
616283
Clinvar variants
Variants in PUS3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

8 Sep 2025, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PUS3 were changed from Global developmental delay; Microcephaly; Mental retardation, autosomal recessive 55, 617051; Intellectual disability to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051

25 Jul 2019, Gel status: 3

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

Catherine Snow (Genomics England)

Source Expert Review Green was added to PUS3. Source Expert Review was added to PUS3. Added phenotypes Mental retardation, autosomal recessive 55, 617051 for gene: PUS3 Publications for gene PUS3 were changed from 27055666; 30308082 to 30697592; 30308082; 27055666 Rating Changed from No List (delete) to Green List (high evidence)

10 Dec 2018, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: PUS3 was added gene: PUS3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PUS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PUS3 were set to 27055666; 30308082 Phenotypes for gene: PUS3 were set to Global developmental delay; Intellectual disability; Microcephaly Penetrance for gene: PUS3 were set to Complete Review for gene: PUS3 was set to AMBER gene: PUS3 was marked as current diagnostic