Beyond screening for chromosomal abnormalities: Advances in non-invasive diagnosis of single gene disorders and fetal exome sequencing

Abstract

Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities. In addition, the transformation of prenatal genetic testing arising from the introduction of whole genome, exome and targeted NGS produces unprecedented volumes of data requiring complex analysis and interpretation. Now translating these technologies to the clinic has become the goal of clinical genomics, transforming modern healthcare and personalized medicine. The achievement of this goal requires the most progressive technological tools for rapid high-throughput data generation at an affordable cost. Furthermore, as larger proportions of patients with genetic disease are identified we must be ready to offer appropriate genetic counselling to families and potential parents. In addition, the identification of novel treatment targets will continue to be explored, which is likely to introduce ethical considerations, particularly if genome editing techniques are included in these targeted treatments and transferred into mainstream personalized healthcare. Here we review the impact of NGS technology to analyse cell-free DNA (cfDNA) in maternal plasma to deliver NIPD for monogenic disorders and allow more comprehensive investigation of the abnormal fetus through the use of exome sequencing.