PRENATAL DIAGNOSIS - INDIVIDUALS AND SOCIETY
Oslo, December 2-3, 2010
How do we deal with uncertain information?
Jón Jóhannes Jónsson
Department of Biochemistry and Molecular Biology, University of Iceland Medical School and
Department of Genetics and Molecular Medicine, Landspitali-National University Hospital;
Reykjavik, Iceland
In the presentation I will offer a perspective of an academic medical geneticist. I will discuss
new techniques that allow collection of comprehensive genetic information on individuals
including in prenatal diagnosis. In particular I will focus on whole genome sequencing (WGS).
The cost of WGS is falling rapidly. The technique is currently being used to sequence
thousands of individual human genomes for research and it will also be used in health care in
the not to distant future. It is even proposed that determining a person's genome sequence
will become a routine test.
We don’t at this junction comprehend the extent and significance of the human
genomic variation. In early clinical applications of WGS we are likely to be faced with new
genetic variation including millions of SNP, hundreds of thousands of insertion/deletion
polymorphisms and thousands of structural variants. The functional significance of recurrent
variations is expected to be eventually sorted out. However, given the accuracy of DNA
replication and the number of cell divisions between zygote and gametes it is expected that
each individual has on the order of 50-100 de novo mutations in the constitutional DNA. Many
of these are private and eventually eliminated in future generations. In addition, there are
countless different mutations in somatic cells. The reliable interpretation of their significance
will require a deeper understanding of the variation in the genome.
In short, the advise to those considering clinical WGS is: Be careful. You will be faced
with thousands of novel sequence variants of uncertain clinical significance, We most often
don’t know how to interpret their significance. Take for instance missense mutations.
Thousands will be present in a genomic sequence. One can look at whether it is a known
mutation in a database, evaluate the change in chemical class of amino acids, analyze
whether the change involves a critical site, or if the sequence is conserved by interspecies
comparison. Computer programs are available to assist in this work. One can also do
segregation studies of the variation in the family. These methods are sometimes but not
always able to predict pathogenicity as will be illustrated with examples from my own practice.
WGS by its nature involves diagnostic testing, predictive testing, susceptibility testing,
pharmacogenetic testing, and carrier testing all in one. The pre- and post-test genetic
counseling will be time consuming and complex as will the postanalytical phase of assigning
significance to the findings and reporting them. In genetic counseling one needs to be nondirective, yet empathetic and caring. The duty to inform is difficult to fulfill in the WGS setting.
One also needs to be aware of heuristic techniques and how they affect rational decision
making. The associated work is likely to cost much more than the expected $1000 for
determining the sequence!
Clinical WGS will presumably first be applied to individuals with serious conditions,
which are presumably genetic, but have resisted conventional diagnostic measures. The
need to understand the condition, establish prognosis, plan therapy as well as to determine
recurrence risks is very strong. Often this need will be stronger than any possible
disadvantage of WGS. Medical geneticists are currently regularly faced with distressed
families where a diagnosis could not be made. They look forward to adding WGS to their
armamentarium. Eventually WGS will also be used in prenatal diagnosis which is a difficult
application. The added dilemma here is that everyone has faulty genes with negative impact
on health. Defining values and goals for WGS in prenatal diagnosis will therefore be
paramount.