Genome-wide noninvasive prenatal diagnosis of monogenic disorders: Current and future trends

Abstract

Noninvasive prenatal diagnosis (NIPD) is a risk-free alternative to invasive methods for prenatal diagnosis, e.g. amniocentesis. NIPD is based on the presence of fetal DNA within the mother's plasma cell-free DNA (cfDNA). Though currently available for various monogenic diseases through detection of point mutations, NIPD is limited to detecting one mutation or up to several genes simultaneously. Noninvasive prenatal whole exome/genome sequencing (WES/WGS) has demonstrated genome-wide detection of fetal point mutations in a few studies. However, Genome-wide NIPD of monogenic disorders currently has several challenges and limitations, mainly due to the small amounts of cfDNA and fetal-derived fragments, and the deep coverage required. Several approaches have been suggested for addressing these hurdles, based on various technologies and algorithms. The first relevant software tool, Hoobari, recently became available. Here we review the approaches proposed and the paths required to make genome-wide monogenic NIPD widely available in the clinic.

Keywords: Genome-wide; Monogenic disorders; NIPD; NIPT; Noninvasive prenatal diagnosis.

Graphical abstract

Fig. 1

Trends in NIPD of monogenic diseases.

Fig. 2

A timeline of milestone methods for NIPD of monogenic diseases.

Fig. 3

Two main approaches for genome-wide noninvasive fetal genotyping. The parental diploid genomes are represented as parallel lines, with the parental genotype in maternal-only heterozygous loci (the father is homozygous). Zero and one represent the reference and alternate alleles, respectively. 0/0 and 0/1 represent homozygous and heterozygous genotypes, respectively. Red and blue colors represent the two maternal haplotypes. In the haplotype-based approach, the maternal genome is phased through various methods, and this enables inference of the fetal haplotypes. For biparental loci, i.e. sites in which both parents are heterozygous, haplotyping of both parents is required (not shown here). In the site-by-site approach, deeper sequencing replaces the requirement for haplotype information, thus the fetus is genotyped, but its haplotypes are not deduced. This method is applicable for biparental loci. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)