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Intellectual disability

Gene: IMPDH2

Green List (high evidence)
IMPDH2 (inosine monophosphate dehydrogenase 2)
EnsemblGeneIds (GRCh38): ENSG00000178035
EnsemblGeneIds (GRCh37): ENSG00000178035
OMIM: 146691, Gene2Phenotype
IMPDH2 is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
Created: 14 Mar 2022, 2:22 p.m.
Last Modified: 14 Mar 2022, 2:22 p.m.
Panel version: 3.1519

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: New gene added by Zornitza Stark. This gene is not yet associated with a relevant phenotype in OMIM or G2P, but sufficient unrelated cases with relevant phenotype to rate Green at the next GMS review. Neurodevelopmental delay is an early feature that may be evident prior to other manifestations (plausible that other cases may develop dystonic signs later in life) and so inclusion on this panel is warranted.
Created: 22 Sep 2021, 2:42 p.m. | Last Modified: 22 Sep 2021, 2:42 p.m.
Panel Version: 3.1300
Zech et al., 2020 (PMID: 33098801) reported on 6 unrelated individuals with de novo variants (4 missense, 1 deletion) in the IMPDH2 gene. All patients had a neurodevelopmental disorder with DD and variable ID. 5/6 cases displayed gait disturbances and impaired motor control but only 2 individuals had dystonia while the others did not present indication of an overt movement disorder.
Created: 22 Sep 2021, 2:41 p.m. | Last Modified: 22 Sep 2021, 2:41 p.m.
Panel Version: 3.1299

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

Publications

Created: 22 Sep 2021, 2:41 p.m.
Last Modified: 22 Sep 2021, 2:41 p.m.
Panel version: 3.1299

Zornitza Stark (Australian Genomics)

Green List (high evidence)

6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

All individuals shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing.

Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Created: 7 Aug 2021, 1:52 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder with dystonia

Publications

Created: 7 Aug 2021, 1:52 a.m.

Panel version: 3.1216

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Neurodevelopmental disorder with dystonia
OMIM
146691
Clinvar variants
Variants in IMPDH2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

14 Mar 2022, Gel status: 3

Removed Tag

Ivone Leong (Genomics England Curator)

Tag Q3_21_rating was removed from gene: IMPDH2.

14 Mar 2022, Gel status: 3

Added New Source, Status Update

Ivone Leong (Genomics England Curator)

Source Expert Review Green was added to IMPDH2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

22 Sep 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: impdh2 has been classified as Amber List (Moderate Evidence).

22 Sep 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_21_rating tag was added to gene: IMPDH2.

7 Aug 2021, Gel status: 0

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

Zornitza Stark (Australian Genomics)

gene: IMPDH2 was added gene: IMPDH2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IMPDH2 were set to 33098801 Phenotypes for gene: IMPDH2 were set to Neurodevelopmental disorder with dystonia Review for gene: IMPDH2 was set to GREEN