Genetics of Learning Disability (GOLD)

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Information for Clinicians

The GOLD Study was established in 2001 and has recruited more than 800 families throughout the UK, Europe, USA and Australia. With a particular focus on the X chromosome, we aim to identify mutations in novel genes that result in significant intellectual disability in humans and to better understand the mechanisms by which intellectual disability occurs.

Two strategies have been used to identify the disease-causing genes:

i) systematic large-scale sequencing of X chromosome genes

ii) sequence characterization of the breakpoints of apparently balanced reciprocal X;autosome translocations.

In collaboration with The Wellcome Trust Sanger Institute, we have pioneered a high-throughput approach to disease gene identification using systematic searches for mutations across the whole of the coding X chromosome. This approach allows gene identification in diseases such as intellectual disability where phenotypic and genetic heterogeneity can limit the utility of linkage-based and candidate gene approaches.

In total, approximately 1 Mb of X chromosome sequence has been analysed for one affected individual from each of >200 families with various forms of intellectual disability. To date, this project has identified 12 new genes with mutations causing X-linked intellectual disability and has also contributed to the discovery of four additional genes. Comprehensive phenotypic information has been invaluable and has led to the identification of a number of new syndromes.  We have recently published an overview of the results of the exon re-sequencing project titled 'A systematic, large-scale resequencing schreen of X-chromosome coding exons in mental retardation'. We have also used high-resolution microarrays to assess the contribution of sub-microscopic deletions and duplications. We are continuing to mine the sequence and copy number data with the hope of identifying the more cryptic causative variants.

Whilst the X chromosome re-sequencing project was a considerable undertaking, the development of massively parallel sequencing means that it now serves as a pilot study for the analyses of whole genomes and expanded cohorts of individuals. Our future work will exploit the emerging sequencing technologies as we continue to investigate the genetic causes of intellectual disability.

 

Future Work

We are now looking to expand our cohort of families and affected individuals further to create a resource which would be useful to the intellectual disability research community as a whole. The power of the cohort to date has been the availability of high quality DNA together with good clinical data, where patients have been reviewed by clinical geneticists.

We are aiming to collect DNA samples from 2000 families and singletons with intellectual disability who are consented for research. This cohort will be available to screen candidate genes both on the X chromosome and autosomes. We are requesting DNA from families where there is one or more males affected with intellectual disability together with:

(i) no molecular diagnosis as assessed by experienced clinical geneticists

(ii) a normal karyotype (500G-banding)

(iii) exclusion of Fragile X syndrome