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Shoubridge C.,Genetics and Molecular Pathology | Shoubridge C.,University of Adelaide | Tarpey P.S.,Wellcome Trust Sanger Institute | Abidi F.,Jc Self Research Institute | And 19 more authors.
Nature Genetics | Year: 2010

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing. © 2010 Nature America, Inc. All rights reserved.

Shoubridge C.,Womens and Childrens Hospital | Shoubridge C.,University of Adelaide | Gardner A.,Womens and Childrens Hospital | Schwartz C.E.,Jc Self Research Institute | And 4 more authors.
European Journal of Human Genetics | Year: 2012

Intellectual disability is common. Aristaless-related homeobox (ARX) gene is one of the most frequently mutated and pleiotropic genes, implicated in 10 different phenotypes. More than half of ∼100 reported cases with ARX mutations are due to a recurrent duplication of 24 bp, c.429-452dup, which leads to polyalanine tract expansion. The excess of affected males among the offspring of the obligate carrier females raised the possibility of transmission ratio distortion for the c.429-452dup mutation. We found a significant deviation from the expected Mendelian 1:1 ratio of transmission in favour of the c.429-452dup ARX mutation. We hypothesise that the preferential transmission of the c.429-452dup mutation may be due to asymmetry of meiosis in the oocyte. Our findings may have implications for genetic counselling of families segregating the c.429-452dup mutation and allude to putative role of ARX in oocyte biology. © 2012 Macmillan Publishers Limited All rights reserved.

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