Cell-free fetal DNA analysis for non-invasive prenatal screening of fetal 
chromosomal aneuploidy has been widely adopted for clinical use. Fetal monogenic 
diseases have also been shown to be amenable to non-invasive detection by 
maternal plasma DNA analysis. A number of recent technological developments in 
this area has increased the level of clinical interest, particularly as one 
approach does not require customized reagents per mutation. The mutational 
status of the fetus can be assessed by determining which parental haplotype that 
fetus has inherited based on the detection of haplotype-associated SNP alleles 
in maternal plasma. Such relative haplotype dosage analysis requires the input 
of the parental haplotype information for interpretation of the fetal 
inheritance pattern from the maternal plasma DNA data. The parental haplotype 
information can be obtained by direct means, reducing the need to infer 
haplotypes using DNA from other family members. The technique also allows the 
assessment of complex mutations and has multiplexing capabilities where a number 
of genes and mutations can be assessed at the same time. These advantages allow 
non-invasive prenatal diagnosis of fetal monogenic diseases to be much more 
scalable. These applications may drive the next wave of clinical adoption of 
cell-free fetal DNA testing. © 2018 The Authors Prenatal Diagnosis Published by 
John Wiley & Sons Ltd.