Hereditary Disease Clinical Trial
Official title:
NON-INVASIVE PRENATAL TESTING (NIPT) OF FETAL SINGLE-GENE DISORDERS IN MATERNAL BLOOD
Developing a new non-invasive prenatal test for single gene disorders from cell free fetal DNA, retrieved from the mothers blood.
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.
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