Non Invasive Prenatal Testing (NIPT) of Single-gene Disorders

Rationale: Conventional prenatal diagnosis (PND) for single-gene disorders requires invasive procedures, either chorionic villus sampling between 11 and 14 weeks gestation or amniocentesis after 15 weeks. Although these approaches to obtain foetal DNA currently provide the golden standard for PND, the invasive procedures carry a risk of miscarriage of 0.5-1%. A reliable non-invasive alternative has long been sought. Circulating cell-free foetal (cff) nucleic acids (DNA and RNA), which are present in maternal blood during pregnancy, can be used for non-invasive prenatal testing (NIPT). NIPT for some chromosomal anomalies (trisomy 21, 13, 18) is now validated. NIPT for other chromosomal anomalies is still under development. NIPT of single-gene disorders is technically very challenging, due to the predominance of maternal DNA sequences, Some small studies have shown that a very limited number of monogenic genetic disorders can currently be diagnosed in maternal blood. In general de novo mutations in the foetus and paternally transmitted disorders are less difficult to diagnose than maternally transmitted disorders.

In this study, the investigators aim to develop non-invasive targeted molecular analysis using cell free fetal (cff) DNA and cff RNA for single-gene disorders, in pregnant women referred to the departments of Clinical Genetics of Maastricht University Medical Centre (MUMC+) and Radboud University Medical Centre (RUMC) for conventional PND. The investigators will contribute to literature by confirming earlier published results, and by adding other single-gene disorders or mutations to the list of disorders for which the possibility of the use of cff DNA will be examined.

Objective: Developing targeted non-invasive prenatal analysis for single-gene disorders using cff DNA and RNA in maternal plasma.

Study design: This study is a proof of concept study in which we aim to demonstrate that molecular analysis can indicate the presence or absence of (a) mutant allele(s) in maternal plasma.

Study population: Pregnant women (≥18y) referred to the Department of Clinical Genetics of MUMC+ or RadboudUMC for conventional PND, for one of the following reasons:

• The fetus is at high risk of having inherited a dominant or recessive disorder of his/her affected parent(s).
• The fetus at risk of having a de novo disorder on the basis of ultrasonography findings.

Main study endpoints: Does targeted molecular analysis of cff DNA and RNA indicate

1. the presence or absence of (a) mutant allele(s) in maternal plasma
2. the presence of a sufficient concentration of foetal nucleic acids in the maternal plasma to reliably diagnose the monogenic disorder Nature and extent of the burden and risks associated with participation and benefit: minimal burden: one moment of blood sampling for the pregnant woman and her partner. In most cases the blood sampling will be combined with regular blood sampling. Benefit: no benefit for this pregnancy as in the study phase the result of the invasive prenatal test is leading.