Orit Reish and Tod Fullston contributed equally to this work.
Version of Record online: 15 JUL 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 149A, Issue 8, pages 1655–1660, August 2009
How to Cite
Reish, O., Fullston, T., Regev, M., Heyman, E. and Gecz, J. (2009), A novel de novo 27 bp duplication of the ARX gene, resulting from postzygotic mosaicism and leading to three severely affected males in two generations. Am. J. Med. Genet., 149A: 1655–1660. doi: 10.1002/ajmg.a.32842
How to cite this article: Reish O, Fullston T, Regev M, Heyman E, Gecz J. 2009. A novel de novo 27 bp duplication of the ARX gene, resulting from postzygotic mosaicism and leading to three severely affected males in two generations. Am J Med Genet Part A 149A:1655–1660.
- Issue online: 23 JUL 2009
- Version of Record online: 15 JUL 2009
- Manuscript Accepted: 11 MAR 2009
- Manuscript Received: 2 SEP 2008
- Australian NHMRC Program Grant
- infantile spasms;
- 27 bp duplication;
- polyalanine tract;
The Aristaless Related Homeobox (ARX) gene is a Q50 paired homeobox gene. These genes are important regulators of essential events during vertebrate embryogenesis, including the development of the central and peripheral nervous system. Mutations in ARX have been identified in at least 82 different families and sporadic cases, and are responsible for at least 8 clinically distinct disorders. The recurrent 24 bp duplication (dup) mutation, c.429_452dup(24 bp), is the most frequent ARX mutation, which accounts for 45% of all cases reported to date. Here we report a novel de novo, familial dup mutation of 27 bp, c.430_456dup(27 bp), which involves the same region of the ARX gene in exon 2, as the dup24 bp mutation. The female progenitor of this dup27 bp allele exhibits mosaicism, likely resulting from a postmitotic de novo mutation event early in embryonic development. Three males with the dup27 bp mutation presented with infantile spasms, two of whom died early in life. Their phenotype appeared more severe, when compared to the spectrum of clinical presentations associated with the dup24 bp mutation. We propose that this might be at least partly due to the single, extra alanine residue (A) (21A in dup27 vs. 20A in dup24), which takes polyalanine tract 2 of ARX beyond the maximum, naturally occurring limit of 20A found in the human genome. © 2009 Wiley-Liss, Inc.