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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

Authors

  • Orit Reish,

    1. Genetic Institute, Assaf Harofeh Medical Center, Zerifin, Israel
    2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Tod Fullston,

    1. SA Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia
    2. Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia
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  • Miriam Regev,

    1. Genetic Institute, Assaf Harofeh Medical Center, Zerifin, Israel
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  • Eli Heyman,

    1. Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel
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  • Jozef Gecz

    Corresponding author
    1. SA Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia
    2. Department of Paediatrics, The University of Adelaide, Adelaide, South Australia, Australia
    • Department of Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia.

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  • Orit Reish and Tod Fullston contributed equally to this work.

  • 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.

Abstract

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.

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