Childhood onset dystonia, chorea or related movement disorder

Gene: IMPDH2

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 14 Mar 2022, 10:59 a.m. | Last Modified: 14 Mar 2022, 10:59 a.m.

Panel Version: 1.217

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 4:45 p.m. | Last Modified: 3 Mar 2022, 4:45 p.m.

Panel Version: 1.212

Green List (high evidence)

Comment on list classification: This gene is not yet associated with a relevant phenotype in OMIM or G2P, but there are sufficient unrelated cases (3) presenting with signs of dystonia to rate as Green at the next GMS review. Other cases reported with motor dysfunction, and it is plausible that this may develop into dystonia later in life.

Created: 22 Sep 2021, 2:59 p.m. | Last Modified: 22 Sep 2021, 2:59 p.m.

Panel Version: 1.155

Kuukasjärvi et al., 2021 (PMID: 34305140) report on an additional large Finnish family (6 affected members) with a heterozygous truncating variant co-segregating with a dominantly inherited dystonia-tremor phenotype. Patient fibroblasts showed reduced IMPDH2 expression. IMPDH2 is the rate-limiting enzyme in the biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders.

Created: 22 Sep 2021, 2:56 p.m. | Last Modified: 22 Sep 2021, 2:56 p.m.

Panel Version: 1.154

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

• 33098801
• 34305140

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

• 33098801