Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep 14:18:2463-2470.
doi: 10.1016/j.csbj.2020.09.003. eCollection 2020.

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

Tom Rabinowitz  1 , Noam Shomron  1
Affiliations
Review

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

Tom Rabinowitz et al. Comput Struct Biotechnol J. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The Shomron Laboratory is supported by the Israel Science Foundation (ISF; 1852/16); Israeli Ministry of Defense, Office of Assistant Minister of Defense for Chemical, Biological, Radiological and Nuclear (CBRN) Defense; Foundation Fighting Blindness; The Edmond J. Safra Center for Bioinformatics at Tel Aviv University; Zimin Institute for Engineering Solutions Advancing Better Lives; Eric and Wendy Schmidt Breakthrough Innovative Research Award; Tel Aviv University Richard Eimert Research Fund on Solid Tumors; Djerassi-Elias Institute of Oncology; Canada-Montreal Friends of Tel Aviv University; Harold H. Marcus; Amy Friedkin; Natalio Garber; Kirschman Dvora Eleonora Fund for Parkinson's Disease; Joint funding between Tel Aviv University and Yonsei University; Israeli Ministry of Science and Technology, Israeli–Russia joint funding; Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease; and a generous donation from the Adelis Foundation.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Trends in NIPD of monogenic diseases.
Fig. 2
Fig. 2
A timeline of milestone methods for NIPD of monogenic diseases.
Fig. 3
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.)
See this image and copyright information in PMC

References

    1. Agarwal K., Alfirevic Z. Pregnancy loss after chorionic villus sampling and genetic amniocentesis in twin pregnancies: a systematic review. Ultrasound Obstet Gynecol. 2012;40(2):128–134. - PubMed
    1. Akolekar R., Beta J., Picciarelli G., Ogilvie C., D’Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015;45(1):16–26. - PubMed
    1. Fan H.C., Blumenfeld Y.J., Chitkara U., Hudgins L., Quake S.R. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci USA. 2008;105(42):16266–16271. - PMC - PubMed
    1. Lo Y.M.D., Lun F.M.F., Chan K.C.A., Tsui N.B.Y., Chong K.C., Lau T.K. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc Natl Acad Sci USA. 2007;104(32):13116–13121. - PMC - PubMed
    1. Hill M., Finning K., Martin P., Hogg J., Meaney C., Norbury G. Non-invasive prenatal determination of fetal sex: translating research into clinical practice. Clin Genet. 2011;80(1):68–75. - PubMed

LinkOut - more resources