Fig. 1: Principles of cell-free fetal DNA (cffDNA) haplotyping.
From: Noninvasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA
(a) Example of a family with an autosomal dominant disorder. DNA from the parents and the affected offspring is first genotyped and on the basis of the affected child’s genotype, parental single-nucleotide polymorphisms (SNPs) can be phased to determine the transmission of paternal and maternal homologs, including the mutant allele. Paternal informative SNPs, defined as heterozygous in the father and homozygous in the mother, are identified as a step 1 phasing rule. The paternal homolog that is transmitted to the affected child must contain the causative variant and is denoted homolog 1 (H1), whereas paternal H2 carries the normal allele. Subsequently (step 2), informative SNPs are categorized to define parental SNPs subcategories—P1 and P2 for paternal SNPs, and M1 and M2 for maternal SNPs. (b) Determination of fetal haplotype inheritance was based on fetal allele ratio (FAR) metric. Red and blue indicate paternal P1 and P2 SNP subcategories, and the same color code is also applied to distinguish M1 and M2 SNP subcategories. Segmentation on FAR values (step 3) was performed to define the haplotype blocks derived from paternal H1 and H2 or maternal H1 and H2, thus indicating homologous recombination sites between the parental H1 and H2.
