Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia

Australia

Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia

Australia
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Krishnaraj R.,Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia | Ho G.,University of Sydney | Christodoulou J.,Murdoch Childrens Research Institute
Human Mutation | Year: 2017

Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that primarily affects females. Mutations in the MECP2 gene have been attributed as the major genetic cause of RTT. Recently, mutations in CDKL5 and FOXG1 genes have also been suggested to give rise to RTT, although subsequent more extensive studies suggest that diseases resulting from mutations in these two genes should be considered as distinct clinical entities. While the genetic basis for the RTT has been recognized, so far there is no effective cure for the disease and the treatments available are mainly aimed at ameliorating clinical problems associated with the disorder. The swift identification of the mutations in children is crucial for pursuing the best therapeutic care. RettBASE was created in 2002 as a MECP2 variant database and has grown to become a comprehensive variant database for RTT and related clinical phenotypes, containing a curated collection of variants for MECP2, CDKL5, and FOXG1 genes. Here, we describe the development and growth of RettBASE after its inception in 2001. Currently, RettBASE holds a total of 4,668 variants in MECP2, 498 variants in CDKL5, and 64 variants in FOXG1. © 2017 Wiley Periodicals, Inc.


Smith T.,University of Sussex | Ho G.,Center for Rett Syndrome Research Western Sydney Genetics Program Childrens Hospital at Westmead Sydney Australia | Christodoulou J.,University of Sydney | Price E.A.,Retinoblastoma Genetic Screening Unit Barts Health NHS Trust The Royal London Hospital 80 Newark Street London United Kingdom | And 8 more authors.
Human Mutation | Year: 2016

We have investigated whether the mutation rate varies between genes and sites using de novo mutations (DNMs) from three genes associated with Mendelian diseases (RB1, NF1, and MECP2). We show that the relative frequency of mutations at CpG dinucleotides relative to non-CpG sites varies between genes and relative to the genomic average. In particular we show that the rate of transition mutation at CpG sites relative to the rate of non-CpG transversion is substantially higher in our disease genes than amongst DNMs in general; the rate of CpG transition can be several hundred-fold greater than the rate of non-CpG transversion. We also show that the mutation rate varies significantly between sites of a particular mutational type, such as non-CpG transversion, within a gene. We estimate that for all categories of sites, except CpG transitions, there is at least a 30-fold difference in the mutation rate between the 10% of sites with the highest and lowest mutation rates. However, our best estimate is that the mutation rate varies by several hundred-fold variation. We suggest that the presence of hypermutable sites may be one reason certain genes are associated with disease. © 2016 Wiley Periodicals, Inc.

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