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Editor’s comment: Prof. Yves Ville: Non-invasive whole fetal genome sequencing : Putting the cart before the horse ?

The development of next-generation sequencing (NGS) technologies (ie, new high-throughput and massively parallel DNA sequencing technologies) has substantially reduced both the cost and the time required to sequence an entire human genome.  Its application to the human fetus has become a reality that is close to clinical implementation. (Lefkowitz R. et al) It is therefore both critical and urgent to be prepared for a shift in paradigm in prenatal screening and diagnosis.

Although this has been a technical breakthrough, the non-invasive access to the fetal genome does not constitute the actual medical revolution. Non-invasiveness is « only » breaking the already fragile barrier made of the risk of miscarriage related to invasive testing (IT).

The bright side of non invasive fetal genome sequencing (NIFGS) is the increased reassurance about a large number of Mendelian disorders in high risk families and in families who would not otherwise have been offered prenatal testing, or who would have refused invasive testing because of the risks to the pregnancy and the fetus. However with current risks of fetal loss following IT consistantly being reported to be closer to 1/1,000 than to 1/100, it is becoming apparent that NIPT is now alleviating more  taboos than medical barriers.

Indeed, to a large extent NIPT will mirror what has been happening for some time in testing of infants and children.  For example, microarray studies and whole genome sequencing can yield copy-number variations of unknown clinical meaning or variants that cause varying  phenotypes.  However, in the prenatal setting, the stakes are higher for at least two reasons :

1.   Information on fetal phenotype to be confronted with genotype of uncertain prognosis or even significance is very likely to be insufficient. Therefore counselling is unlikely to be as objective and convincing as that provided by pediatric geneticists exploring the prospect of both pediatric and adult complex disease.  Pregnant women  may rather consider terminating the pregnancy based up on « abnormal » results although these will not always translate into a severe condition or even into any disease.

2.   Access to thorough genetic advice and counselling is likely to be impossible more often than not, due already overwhelmed specialized ressources but also the lack of specific knowledge of how to interpret such information.

The main difference with today’s prenatal testing is therefore a complete disconnexion between phenotype and genotype and the precedence of genotype information over phenotype. The main consequence of puting the cart before the horse is likely to be … Confusion. Societal pressure might therefore threaten parental autonomy over reproductive decision-making and at least raise unfounded parental anxiety. In all, this change in paradigm for prenatal testing is very likely to lead to an increase in elective terminations, both for disorders previously or newly tested for but also for a wide range of traits and susceptibility genes.


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Commentaries by Editor Prof. Jim Thornton