A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Nature Genetics (Impact Factor: 29.65). 05/2009; 41(5):535-43. DOI: 10.1038/ng.367
Source: PubMed

ABSTRACT Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.

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Available from: Jozef Gecz, Jul 28, 2015
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    • "Several attempts have been made in the recent past to accelerate the discovery of novel neurological disease genes. One of the earliest attempts was the high-throughput Sanger sequencing of all coding exons on the X chromosome in a large cohort of >200 families with suspected X-linked intellectual disability (Tarpey et al., 2009). In addition to the laborious nature of this approach, the yield was somewhat modest (three novel genes) partly because enrichment for novel gene discovery was not feasible, and also partly due to a large proportion of X-linked disease genes having already been established (de Brouwer et al., 2007). "
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    ABSTRACT: Neurogenetic disorders represent the largest category of Mendelian diseases in humans. They encompass a wide array of clinical presentations that range from the common e.g., intellectual disability (>1%) to the very rare, e.g., neurodegeneration with brain iron accumulation (one to three per 106) (Kalman et al., 2012 and Maulik et al., 2011). The highly prevalent involvement of the nervous system in many Mendelian disorders coincides with the observation that >80% of all human genes are expressed at some stage of brain development (Hawrylycz et al., 2012) and suggests that the brain is one of the most vulnerable organs to genetic perturbation. In fact high-resolution microarray analysis of the human genome reveals that intellectual disability is the common phenotypic denominator of genomic disorders that involve losses or gains of genes (Coe et al., 2012).
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    • "Both mutations are located in the same stretch of cytosine of exon 10 that is prone to generate errors during the DNA replication by slippage mechanism [Fusco et al., 2008]. The p.Asp113Asn (c.337G>A, exon3) was described as a polymorphic variant of the IKBKG gene in Fusco et al. (2004) and, more recently, in Tarpey et al. (2009). Moreover, in Salt et al. (2008) "
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    ABSTRACT: Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at
    Human Mutation 02/2014; 35(2). DOI:10.1002/humu.22483 · 5.05 Impact Factor
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    • "In addition, this variant is highly conserved (GERP++ score >5), and the unaffected female is not a carrier of this mutation. Interestingly, the mutation in SLC9A6 (p.R536Q) has already been observed in a study on mental retardation (Tarpey et al. 2009), and other mutations on this gene have been associated with mental retardation, ataxia, and epilepsy (Online Mendelian Inheritance in Man [OMIM]: 300231, Mental Retardation, X-linked, syndromic, Christianson-type; MRXSCH) (Gilfillan et al. 2008). This mutation was subsequently found in a healthy uncle, making its clinical significance unclear. "
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