fig2

Figure 2. Relative mutation dosage (RMD) analysis for NIPD of maternally inherited pathogenic variants. A: Schematic depicting the relative mutation dosage (RMD) approach taken for NIPD of autosomal recessive conditions where the parents are both heterozygous carriers (het) for the same pathogenic variant at the same genetic locus. A balance or decrease in the quantity of the pathogenic variant (relative to the wildtype (WT) variant) indicates that the fetus is unaffected (scenarios one and two). An increase in the pathogenic variant indicates that the fetus is affected (scenario three). B: Schematic depicting the RMD approach taken for NIPD of autosomal recessive conditions where the parents are het for different pathogenic variants at different loci within the gene of interest. Testing for the paternal pathogenic variant can be carried out prior to RMD, whereby if it is not present (undetected), the fetus is unaffected (scenarios one and two). If detected, RMD can be performed. A decrease in the maternal pathogenic variant indicates that the fetus is unaffected (scenario three), while a balance indicates that the fetus is a compound het (comp het), and thus affected (scenario four). A similar approach can be taken for parents carrying different pathogenic variants at the same genetic locus (not shown), where dosage analysis of the maternal variant can be carried out if the paternal pathogenic variant is detected (similar to scenario three in A). C: For autosomal dominant conditions where the mother is het affected and the father homozygous (hom) unaffected, a decrease in the maternal pathogenic variant indicates that the fetus is hom unaffected (scenario one), while a balance between the pathogenic and WT allele indicates that the fetus is het affected (scenario two). D: For X-linked recessive or dominant conditions where the mother is het (carrier or affected, respectively), a decrease in the maternal pathogenic variant indicates a hemizygous (hemi) unaffected fetus (scenario one), while an increase indicates that the fetus will be hemi affected (scenario two). Confirmation of the fetal fraction is necessary to confirm a negative result where there is a balance in WT and pathogenic variants detected (A-C), or where the paternal pathogenic variant is not detected (B).