Clemens Müller-Reible

Session nine: What is the future for translational research in rare diseases?

Advances in genome analysis: is more always better?

Clemens Müller-Reible - Department of Human Genetics, University of Würzburg

Over the past years, a number of novel technologies for genetic analysis (e.g. next generation sequencing - NGS, analysis of copy number variations - CNV) have led to an unprecedented boost of data in human genetics. These technologies have in common the potential to analyze entire genomes or exomes in a parallel approach thus generating data sets in a week which required months or years of work by conventional methods. As an illustration of their power: NGS has allowed for the identification of new causative genes in nuclear families and even individual patients and CNV can now be applied to the analysis of single cells. Cost and working time have been downscaled to a level which now allows using such technologies in routine genetic diagnostics. While the power and cost-effectiveness are impressive, in the context of diagnostic use in humans these technologies pose a number of questions which should be discussed before a wider application, e.g.:
1) The parallel analysis of an entire genome or exome will incidentally generate data on genes which are unrelated to the clinical question but may have far reaching implications of the patient. This will require new capacities for counselling (qualitative and quantitative) prior to testing and new forms of informed consent.

2) First published reports indicate that these techniques can generate an excess of potentially causative variants in genes known to be related to the clinical phenotype. This challenges the Mendelian concept of monogenic inheritance and poses as yet unsolved problems for interpretation. The individual genetic variability may be so high as to prevent statistical analyses from variant databases (which have not been established yet).

3) The availability of these technologies is likely to further support the trend of using laboratory tests as first-line diagnostics in place of thorough clinical examination. This is even more counter-productive since a detailed clinical phenotype description is likely to remain the best approach to understanding complex genotypes.

The wide application of such screening technologies will affect patients and medical practitioners far beyond the community of medical geneticists. It is, therefore, not too early to start a broad discussion with the aim of reaching a best practice consensus for the application of these techniques.