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Intellectual disability

Gene: RPIA

Green List (high evidence)

RPIA (ribose 5-phosphate isomerase A)
EnsemblGeneIds (GRCh38): ENSG00000153574
EnsemblGeneIds (GRCh37): ENSG00000153574
OMIM: 180430, Gene2Phenotype
RPIA is in 7 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Gene RPIA was identified after an expert review by Konstantinos Varvagiannis. RPIA is associated with Ribose 5-phosphate isomerase deficiency phenotype in OMIM (last curated June 2019) and not in Gen2Phen. ID and DD identified in sufficient unrelated families for RPIA to be rated green on the ID panel.
An additional individual was identified in PMID:31056085 for a homozygous missense variant (c.627G>C;p.Trp209Cys;) to add more evidence for this gene.
Created: 30 May 2019, 1:53 p.m. | Last Modified: 3 Jul 2019, 2:43 p.m.
Panel Version: 0.196

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611.

PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T or p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG or p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548].

PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis.

PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis.

RPIA is included in gene panels for intellectual disability offered by various diagnostic laboratories.

As a result this gene can be considered for inclusion in this panel as green (or amber).

[This gene is also present in the Undiagnosed metabolic disorders gene panel as red. Please consider upgrade based on these further publications.]
Sources: Literature
Created: 9 Dec 2018, 1:40 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Ribose 5-phosphate isomerase deficiency, MIM 608611.


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


Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
  • Ribose 5-phosphate isomerase deficiency, OMIM:608611
Clinvar variants
Variants in RPIA
Panels with this gene

History Filter Activity

26 May 2021, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency, 608611; Ribose 5-phosphate isomerase deficiency, MIM 608611. to Ribose 5-phosphate isomerase deficiency, OMIM:608611

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 RPIA. Source Expert Review was added to RPIA. Added phenotypes ?Ribose 5-phosphate isomerase deficiency, 608611 for gene: RPIA Publications for gene RPIA were changed from 14988808; 20499043; 28801340; 30088433 to 20499043; 31056085; 14988808; 30088433; 28801340 Rating Changed from No List (delete) to Green List (high evidence)

9 Dec 2018, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: RPIA was added gene: RPIA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPIA were set to 14988808; 20499043; 28801340; 30088433 Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611. Penetrance for gene: RPIA were set to unknown Review for gene: RPIA was set to GREEN gene: RPIA was marked as current diagnostic