Childhood onset dystonia, chorea or related movement disorder

Gene: ARX

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval.

Created: 4 May 2024, 6:04 p.m. | Last Modified: 4 May 2024, 6:18 p.m.

Panel Version: 4.3

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Green List (high evidence)

A review by Eldar Dedic (Independent Clinical Genetics Consultant):
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021

Created: 24 Oct 2023, 10:36 a.m. | Last Modified: 24 Oct 2023, 10:37 a.m.

Panel Version: 3.53

PMID: 31324350; 29778428; 23657928; 29343471 report four ARX variants in four unrelated families, where childhood onset dystonia is apparent, together with other phenotypic features.

Created: 24 Oct 2023, 10:35 a.m. | Last Modified: 24 Oct 2023, 10:35 a.m.

Panel Version: 3.53

Publications

• 31324350
• 29778428
• 23657928
• 29343471

Comment on list classification: Promoted from Red to Amber due to review; for further clinical review.

Created: 6 Dec 2019, 5:02 p.m. | Last Modified: 6 Dec 2019, 5:02 p.m.

Panel Version: 0.11

I don't know

Gene is associated with wide spectrum of disease. Partington syndrome has characteristic hand dystonia, but dystonia can be a feature across the ARX spectrum. Appears appropriate for panel but clinical input may be helpful before upgrading. A recurrent variant c.441_464dup may not be detected by clinical exome due to polyalanine tract in exon 2

Created: 9 Jul 2019, 3:59 p.m. | Last Modified: 9 Jul 2019, 3:59 p.m.

Panel Version: 0.10