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  3. IMPDH2
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Intellectual disability syndromic and non-syndromic

Gene: IMPDH2

Green List (high evidence)
IMPDH2 (inosine monophosphate dehydrogenase 2)
EnsemblGeneIds (GRCh38): ENSG00000178035
EnsemblGeneIds (GRCh37): ENSG00000178035
OMIM: 146691, Gene2Phenotype
IMPDH2 is in 3 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder with dystonia

Created: 17 Jul 2021, 3:45 a.m.
Last Modified: 17 Jul 2021, 3:45 a.m.
Panel version: 0.3980

Laura Raiti (Royal Children's Hospital, Melbourne)

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.

The variant carriers 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: 16 Jul 2021, 1:51 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Created: 16 Jul 2021, 1:51 p.m.

Panel version: 0.3978

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

17 Jul 2021, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: impdh2 has been classified as Green List (High Evidence).

17 Jul 2021, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: IMPDH2 were changed from to Neurodevelopmental disorder with dystonia

17 Jul 2021, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: impdh2 has been classified as Green List (High Evidence).

16 Jul 2021, Gel status: 0

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

Laura Raiti (Royal Children's Hospital, Melbourne)

gene: IMPDH2 was added gene: IMPDH2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IMPDH2 were set to PMID: 33098801