PHG Foundation | Exome sequencing uncovers new causes of mental retardation

Exome sequencing uncovers new causes of mental retardation
Analysis of a study published in a science journal | By Dr Caroline Wright | Published 22 November 2010
Study: A de novo paradigm for mental retardation
By: Vissers L.E.L.M. et al. (15 authors total)
In: Nature Genetics
Link: http://dx.doi.org/10.1038/ng.712

What this study set out to do:

Investigate the genetic basis for unexplained mental retardation, caused by de novo mutations in children with a normal karyotype and array-based genome profiling.

How they went about it:

Whole exome sequencing was performed on 10 children with unexplained mental retardation and their parents. On average, nearly 22,000 genetic variants were found per individual, which were reduced to under 6,000 variants each by exclusion of non-coding and intronic variants as well as those that would have no affect on the resulting protein sequence. This number was further reduced by excluding known and likely benign variants, firstly by comparison with databases such as dbSNP to exclude common variation, and secondly by comparison with the parents genomes to exclude inherited variants. Following this process and validation by Sanger sequencing, just 9 candidate causal mutations remained which were assessed for their likely biological function.

Outcome:

After an exhaustive bioinformatics analysis pipeline following exome sequencing, 6 variants were identified in 6 individual children that are likely to be pathogenic based on gene function, evolutionary conservation and likely mutational impact.

Conclusion:

These findings provide strong experimental support for the importance of novel genetic variants arising de novo in the aetiology of severe mental retardation.

Our view:

This clearly written study not only expands the genetic causes of mental retardation in children from de novo copy number variants to include de novo point mutations, but also provides an excellent example of the application of whole exome sequencing to a long standing clinical problem. The analysis pipeline described has implications for both preventative and diagnostic strategies in diseases with a strong heritable component, and is likely to be increasingly fruitful as more comprehensive databases of genomic variation and functional assays are developed.

Further discussion:

The PHG Foundation is currently leading a major project to determine how new rapid sequencing techniques may be used for medical purposes (such as the one set out in this study) and the implications of such developments.
Keywords: Disease Susceptibility (Genetic), Genetic Tests, Testing & Screening
PHG Foundation | Exome sequencing uncovers new causes of mental retardation