Mutations of ARX Are Associated with Striking Pleiotropy and Consistent Genotype-Phenotype Correlation

Mitsuhiro Kato, Soma Das, Kristin Petras, Kunio Kitamura, Ken Ichirou Morohashi, Diane N. Abuelo, Mason Barr, Dominique Bonneau, Angela F. Brady, Nancy J. Carpenter, Karen L. Cipero, Francesco Frisone, Takayuki Fukuda, Renzo Guerrini, Eri Iida, Masayuki Itoh, Amy Feldman Lewanda, Yukiko Nanba, Akira Oka, Virginia K. ProudPascale Saugier-Veber, Susan L. Schelley, Angelo Selicorni, Rachel Shaner, Margherita Silengo, Fiona Stewart, Noriyuki Sugiyama, Jun Toyama, Annick Toutain, Ana Lía Vargas, Masako Yanazawa, Elaine H. Zackai, William B. Dobyns

Research output: Contribution to journalReview articlepeer-review

285 Scopus citations


We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalHuman mutation
Issue number2
StatePublished - 2004
Externally publishedYes


  • ARX
  • Agenesis of the corpus callosum
  • Genital abnormalities
  • Hydranencephaly
  • Lissencephaly, X-linked
  • XLAG


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