Genetic Epilepsy

Gene: ARX

Green List (high evidence)

Poly-Ala expansion – EE and ID phenotypes, no brain abnormalilties (PMID: 21496008, OMIM)
NMD PTCs – Brain abnormailities including hydranencephaly, lissencephaly, Proud syndrome (PMID: 14722918, OMIM).
NMD PTCs in the first ~40aa – West/Otahara syndrome, avoid brain abnormalities due to re-initiation of translation at p.Met41 (PMID: 19738637).
Missense - all phenotypes but less severe, severity depends on variant location and protein conservation at that position (PMID: 14722918).

Affected females with PTCs show agenesis of the corpus callosum. Variable expressivity, some are unaffected - no X skewing found in affected females (PMID: 14722918, PMID: 28150386, PMID: 32519823).

Missense and polyA expansions cause protein mislocalization. More poly-Ala expansion = more mislocalization = more severe phenotype (PMID: 14722918). Loss of DNA binding ability is also reported (OMIM).

Variable pleiotrophy well reported within families. Same mutations are reported with different phenotypes (OMIM).

Created: 9 Oct 2020, 3:01 a.m. | Last Modified: 9 Oct 2020, 3:01 a.m.

Panel Version: 0.4843

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

Phenotypes
Epileptic encephalopathy, early infantile, 1 MIM#308350; Hydranencephaly with abnormal genitalia MIM#300215; Lissencephaly, X-linked 2 MIM#300215; Mental retardation, X-linked 29 and others MIM#300419; Partington syndrome MIM#309510; Proud syndrome MIM#300004

Publications

• PMID: 14722918
• 19738637
• 32519823
• 28150386
• 21496008

Variants in this GENE are reported as part of current diagnostic practice