Noninvasive Prenatal Diagnosis of Single-Gene Diseases: The Next Frontier

Abstract

BACKGROUND Cell-free fetal DNA (cffDNA) is present in the maternal blood from around 4 weeks gestation and makes up 5%–20% of the total circulating cell-free DNA (cfDNA) in maternal plasma. Presence of cffDNA has allowed development of noninvasive prenatal diagnosis (NIPD) for single-gene disorders. This can be performed from 9 weeks gestation and offers a definitive diagnosis without the miscarriage risk associated with invasive procedures. One of the major challenges is distinguishing fetal mutations in the high background of maternal cfDNA, and research is currently focusing on the technological advances required to solve this problem. CONTENT Here, we review the literature to describe the current status of NIPD for monogenic disorders and discuss how the evolving methodologies and technologies are expected to impact this field in both the commercial and public healthcare setting. SUMMARY NIPD for single-gene diseases was first reported in 2000 and took 12 years to be approved for use in a public health service. Implementation has remained slow but is expected to increase as this testing becomes cheaper, faster, and more accurate. There are still many technical and analytical challenges ahead, and it is vital that discussions surrounding the ethical and social impact of NIPD take account of the considerations required to implement these services safely into the healthcare setting, while keeping up with the technological advances.

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

“…Theoretically, all the aforementioned methods can be similarly applied over an NGS panel. However, such panels do not cover the whole genome, and thus, often fail to detect mutations [52] . An intermediate option would be to use WES or wide panels that cover all genes that are known to cause Mendelian diseases.…”

Noninvasive prenatal sequencing for multiple Mendelian monogenic disorders among fetuses with skeletal dysplasia or increased nuchal translucency

“…3,4 Noninvasive prenatal sequencing (NIPS) for single gene related diseases such as β-thalassemia, achondroplasia, thanatophoric dysplasia, and Duchenne muscular dystrophy have also been implemented for clinical testing and research. [5][6][7][8] However, the locus-specific design and probanddependent analysis strategy prevented offering NIPS for concurrently detecting a range of monogenic disorders in the clinical practice.…”

“…It can be an alternative test that serves as screening, diagnosis and pregnancy outcome prediction for these two groups of pregnancies. It is also complementary to conventional genome-wide NIPT for chromosomal abnormalities.Currently, the majority of NIPT strategies for monogenic diseases including those available in the public service are limited to cases in which the familial mutation is known or there is a strong indication of a specific genetic condition based on sonographic findings 5. There is a need to offer screening for a range of single-gene diseases to pregnancies with suspected heterogeneous monogenic disorders such as skeletal dysplasias and NSD.…”

Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading (MeSH) terms in publications

“…We first looked at 10 articles published between 2010 and 2019 that were known to include NIPT as a major topic to see how they were indexed in Medline/PubMed. [4][5][6][7][8][9][10][11][12][13] They were variously indexed as "prenatal diagnosis," "maternal screening tests," or "genetic testing." Since there did not seem to be a consistent indexing for NIPT, we used natural language to find article titles that had any of the following terms as an indicator of relevance: "NIPS," "noninvasive prenatal screening,"…”