Developing targeted non-invasive prenatal analysis for single-gene disorders and chromosomal disorders using cff DNA and RNA in maternal plasma. We will investigate when and how the aberrant cells disappear during prenatal development.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Develop a non-invasive prenatal test for chromosomal and monogenic
abnormalities in the pregnant woman's blood.
Doest targeted/genome-wide molecular analysis of cell-free DNA or RNA indicate:
- the presence or absence of fetal mutation (s) in maternal plasma
- the presence of sufficient concentration of fetal DNA / RNA in maternal
plasma to enable reliable diagnosis of monogenic disorders.
- the presence of aneuploidies, structural abnormalities, and monogenic
disorders
- when and how the aberrant cells disappear during prenatal development
Secondary outcome
NA
Background summary
Conventional prenatal diagnosis (PND) for single-gene disorders and chromosomal
anomalies 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). Although NIPT
of monogenic and chromosomal disorders is technically challenging, due to the
predominance of maternal DNA sequences, several genetic disorders have been
currently diagnosed in maternal blood. In this study, we aim to develop
non-invasive targeted molecular and genome wide analysis using cffDNA and
cffRNA for single-gene disorders and chromosomal anomalies, 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.
Genetic aberrations are highly prevalent in early- stage human embryos,
resulting in mosaic embryos which consist of normal and abnormal cells. The
degree of mosaicism reduces during gestation, resulting in ongoing pregnancies
and healthy live births. It is speculated, that cell lineages containing these
genetic aberrations survive in the trophectoderm, and therefore having no or
little influence on fetal development. Furthermore, euploid blastomeres may
outgrow blastomeres with chromosomal aberrations, resulting in normal
development of the embryo. However, the exact correction mechanisms of
vanishing aberrant cells later in development remains elusive. In this study,
we will try to investigate the etiology of the mechanism of vanishing embryonic
mosaic cells.
Study objective
Developing targeted non-invasive prenatal analysis for single-gene disorders
and chromosomal disorders using cff DNA and RNA in maternal plasma. We will
investigate when and how the aberrant cells disappear during prenatal
development.
Study design
This is a "proof of concept" study. We want to show that molecular genome-wide
analysis can show the presence or absence of a fetal disease in maternal
plasma. Pregnant women who have an increased risk of having a child with a
monogenic disorder or chromosomal abnormality and their partners are asked to
donate blood at 1 to 4 times during pregnancy. Depending on the moment of entry
and willingness of the participants. After birth, we collect placenta and
umbilical cord blood to create genetic profiles of the child and the placenta.
Here, we also look at mosaicism and confirm whether it is present in the child
or the placenta. In addition, we will relate the outcome of the mosaic
examination to the clinical outcome of the pregnancy. Finally, we try to
isolate fetal cells from maternal blood and perform genetic testing of those
cells.
Study burden and risks
Minimal burden: one to max four moments of blood sampling for the pregnant
woman and her partner. In most cases, 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.
P. Debyelaan 25
Maastricht 6202 AZ
NL
P. Debyelaan 25
Maastricht 6202 AZ
NL
Listed location countries
Age
Inclusion criteria
Pregnant women and their partners (18+) of which:
Group 1: the woman is pregnant after PGD for a chromosomal anomaly or monogenic
disorder
Group 2: the fetus is at risk for a chromosomal anomaly because of an adverse
result of regular NIPT testing (Dutch TRIDENT-1 or -2 study) for aneuploidy
with or without additional findings.
Group 3: the foetus is at high risk of having a de novo disorder on the basis
of ultrasonography findings and couple will undergo PND
Group 4: the fetus is at high risk of having inherited a dominant or recessive
disorder of his/her affected parent(s) and couple ask for conventional PND
General:
- the pregnant woman and partner are 18 years or older
- the pregnant woman has sufficient understanding of Dutch language and is
able to give informed consent.
Exclusion criteria
- in the opinion of the treating physician psychological distress is so severe
that asking for participation is not safe.
- the pregnant woman is treated for a malignancy
- patients in group 1 (testing performed with only PCR or OnePGT for monogenic
disorders), group 3 and 4 will be excluded from this study if they do not opt
for NIPT (with/without additional findings) or PND (with at least a QF PCR of
chromosomes 13, 18, 21)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT02339402 |
| CCMO | NL48304.068.14 |