ClinGen Dosage Sensitivity Curation Page

ARX

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12379852 Kitamura et al (2002) described nonsense, frameshift and deletion mutations of ARX in a study of X-linked lissencephaly with abnormal genitalia. Method: Sanger sequencing of known clinical cases. 6 cases had LOF mutations of ARX: 1 - 32 bp deletion within exon 2 resulting in a truncated protein 2 - 1bp deletion within exon 2 resulting in a truncated protein 3 - stop mutation in exon 3 (carrier mother) 4 - 1bp insertion in exon 4 resulting in a truncated protein 5 - deletion of exons 1 & 2 6 - 1bp deletion within exon 4 resulting in a truncated protein
14722918 In a followup paper to Kitamura et al (2002), Kato et al (2004) describe a series of patients with an expanded clinical presentation highlighting pleiotropy of ARX. Method: Sanger sequencing of known clinical cases + RNA studies for splice variants 10 additional LOF cases: 1 - EX2-5del 2 - c.196+2T>C (splice) 3 - c.232G>T (stop) 4 - c.335_368del 5 - c.392_452del 6 - c.617delG 7 - c.619_647del 8 - c.1119+1G>C (splice) 9 - c.1105G>T (stop) 10 - c.1372del G
Many further LOF variants described in the literature including at least 8 de novo LOF variants: 2 in Mirzaa et al. 2013 (PMID:23583054) 1 in Kwong et al. 2015 (PMID:25951140) 1 in Wallerstein et al. 2008 (PMID:18462864) 1 in Jiao et al. 2019 (PMID: 30945278) 1 in Tumiene et al. 2018 (PMID: 29286531) 1 in Bettella et al. 2013 (PMID: 23039062) 1 in Miyata et al. 2009 (PMID: 18842366)

Haploinsufficiency phenotype comments:

Further to the cases presented above, functionals studies provide further support for ARX's association with X-linked developmental disorders. Kitamura et al. 2002 (PMID: 12379852) reported that male embryonic mice with mutations in the ARX developed with small brains. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. Fullenkamp et al. 2008 (PMID: 18835247) demonstrated two disease-associated mutations disrupt the function of Arx as a transcriptional repressor.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.