ClinGen Dosage Sensitivity Curation Page

ARX

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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)

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.