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Determine the genetic profile of a fetus at risk of inheriting beta-thalassaemia, using cell-free DNA circulating in the maternal blood. 

The mother and father were genotyped using a SNP-array, and deep sequencing was performed on cell-free DNA fragments extracted from maternal plasma using next generation sequencing technology. Following alignment of the plasma DNA against a reference human genome, comparison with parental SNPs was used to determine the proportion and size of fetal DNA in the maternal plasma, to infer maternal and paternal inheritance patterns, and to create a genome-wide profile of the fetus.

The entire fetal genome was represented in maternal plasma, comprising just over 11% of cell-free DNA (at 12 weeks gestation). The fetus was found to have inherited the paternal beta-thalassaemia mutation but not the maternal one. 

This proof-of-principle study suggests the feasibility of using genome-wide scanning to construct a fetal genetic map and determine the mutational status of the fetus from maternal plasma. The method could be applied to non-invasive diagnosis of numerous fetal genetic disorders including autosomal recessive conditions that are not currently possible using standard techniques.

Non-invasive prenatal diagnosis would allow couples at risk of passing on an inherited condition to their child to avoid a 1% risk of miscarriage associated with invasive diagnostic tests such as amniocentesis. This pioneering study is the first to produce a genome-wide profile for the fetus from a maternal blood sample, and describes a methodology that is potentially applicable to non-invasive diagnosis of almost any genetic condition, rather than being limited to specific traits (such as the sex of the fetus) like most previous methods. However, before such a test could be offered in the clinic, a much larger study is required to determine the robustness of the technique, and numerous logistical, economic and ethical issues need to be addressed, including how to deal with unexpected or incidental findings.

The PHG Foundation has previously looked at the implications of using cell-free fetal DNA for non-invasive prenatal diagnosis, and is currently leading a project to investigate the impact of new DNA sequencing technologies on clinical practice.