PQG Working Group

Giulio Genovese Senior Computational BiologistHarvard Medical School Chromosomal phasing improves aneuploidy determination in non-invasive prenatal testing at low fetal fractions Non-invasive prenatal testing (NIPT) to detect fetal aneuploidy by sequencing cell-free DNA (cfDNA) in maternal plasma has been broadly adopted. To detect fetal aneuploidies from maternal plasma – where fetal DNA is mixed with far-larger amounts of maternal DNA – NIPT requires a minimum fraction of the circulating cfDNA to be of placental origin, a level which is usually attained beginning at 10 weeks gestational age. We present a framework to leverage chromosomal phase – the arrangement of alleles along homologous chromosomes – to make NIPT analyses more conclusive. We re-analyze data from a singleton pregnant mother who received an inconclusive aneuploidy determination through NIPT due to a fetal DNA fraction of 3.4%. We show that the same laboratory data can be used to conclusively infer the presence of a trisomy 18 fetus when chromosomal phase is taken into account. Key to the effectiveness of the approach we describe is the robustness of allelic fraction estimates to biological and laboratory-process driven noise and the ability of chromosomal phase to integrate quantitative signals across very many polymorphic markers. These results show that chromosomal phase increases the sensitivity of a common laboratory test, an idea that could also have broad application in cfDNA analyses for cancer detection.