Targeted resequencing of the X-chromosome to identify XLMR related variants

6 May 2009

Mental retardation is defined as a disability that leads to severe limitations in both intellectual and adaptive abilities, including social, conceptual and practical skills with onset before 18 years. X-linked mental retardation (XLMR) refers to inherited conditions which are caused by defects in the X-chromosome, the effects of which are seen more severely in males than females. The underlying genetic cause may either be due to mutations in individual genes or large scale deletions, insertions or aneuploidies affecting multiple genes. Approximated 80 genes located on the X-chromosome have been linked with XLMR, the most well known of which is the FRM1 gene involved in fragile X syndrome. However, in many cases of XLMR the causative mutations on the X-chromosome are unknown and it has been postulated that rare mutations in many genes contribute to the condition.

A paper published in Nature Genetics describes a sequencing based approach in order to identify rare variants that lead to XLMR. In their study, Tarpey et al targeted approximately 720 genes on the X-chromosome for resequencing and systematic screening [Tarpey et al (2009) Nat Genet. 41(5):535-43]. DNA from 208 individuals from families with XLMR, as well as control DNA from individuals without mental retardation, was sequenced and screened for variants. Nine genes associated with XLMR were identified and abnormal genes responsible for XMLR in 25% of the families were identified, including three new candidate genes. However, although this strategy led to the identification of some XLMR related genes, a large number of sequence variants were also discovered that were benign; mutations leading to loss of function of some protein coding genes were found in both normal as well as XLMR individuals, suggesting they are compatible with normal existence.   

The inability to detect the genetic cause of disease in 75% of the families was attributed to the difficulties in associating many of the identified variants with disease and also to the possibility that mutations in non-coding regions or in micro-RNA sequences could also contribute to XMLR. In addition, large-scale copy number variations and inversions, which were not examined in this study, may also contribute to the condition.

Comment: Although this targeted resequencing approach was able to identify three new candidate genes, the study also illustrates the difficulties faced in identifying rare variants that cause disease. This is mainly because of the difficulty in differentiating between benign and pathogenic variants, especially when the same phenotype (in this case XLMR) may be a result of many different rare variants. Although sequencing technologies are progressing fast, both this paper and previous resequencing ventures – such as the Ventor and Watson genomes (see previous news) and the identification of an inherited cancer gene (see previous news) – illustrate the large amount of sequence variation present in individual genomes, and highlight the enormous analytical and clinical challenge ahead of finding and validating truly disease causing mutations.


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