Clinical study of two brothers with a novel 33 bp duplication in the ARX gene

Michelle K. Demos, Tod Fullston, Michael W. Partington, Jozef Gécz, William T. Gibson

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Pathogenic variations of the ARX (aristaless-related homeobox) gene are associated with marked phenotypic pleiotropy. These phenotypes are X-linked neurological disorders that include brain and genital malformation and non-malformation syndromes. Typically, malformation phenotypes result from pathogenic variations that are predicted to truncate the ARX protein, or alter residues in the highly conserved homeodomain. While non-malformation phenotypes tend to be caused by pathogenic variations that are predicted to expand the first two polyalanine tracts ofARX, or alter residues outside of the homeodomain. The most common pathogenic variation of the ARX gene is a duplication of 24 bp, c.429-452 dup,which leads to an expansion of the second polyalanine tract of theARXproteinfrom 12 to 20 alanine residues. This pathogenic variation is associated with both sporadic and familial nonsyndromic mental retardation. Syndromic manifestations include mental retardation with hand dystonia (Partington syndrome), infantile spasms (West syndrome) and/or other epileptic seizures. Here, we report on a novel pathogenic variant of a tandem 33 bp duplication that is predicted to result in an expansion of polyalanine tract 2 in two brothers with mental retardation, epilepsy, dystonia, and the novel feature of intermittent hyperventilation. This pathogenic variation is predicted to result in a "non-homogeneous" polyalanine tract expansion that is longer than predicted expansion caused by the common 24 bp duplication. The location of the novel 33 bp duplication in the same region as the common 24 bp duplication supports this region as theARXvariation "hot spot."

Original languageEnglish
Pages (from-to)1482-1486
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Issue number7
Publication statusPublished or Issued - 1 Jul 2009
Externally publishedYes


  • Arx gene
  • Dystonia
  • Polyalanine expansions
  • Seizures

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this