Cystic Fibrosis Clinical Trial
Official title:
Universal Haplotype-Based Non Invasive Prenatal Diagnosis by Linked-Read Sequencing (10XGenomics™ Technology)
Description of the presence of cell-free fetal DNA in maternal plasma allowed the possibility
of non-invasive prenatal diagnosis. Whereas detection of paternally-inherited alleles is
straightforward and being quickly implemented in routine, detection of maternally-inherited
alleles remains challenging.
To date, the main approach that is being developped, called Relative Haplotype Dosage
Analysis, relies on the identification of an allelic imbalance between the mother's wild-type
and mutant alleles, relative to the fetal's contribution. This approach therefore requires
the study of a propositus to identify the morbid haplotype, which is not always possible in
the context of an ongoing pregnancy.
In this study, we aim to evaluate the contribution of new technologies, such as linked-read
Sequencing, to allow direct identification of parental haplotype in the context of
non-invasive prenatal diagnosis.
Objectives:
The description of cell-free fetal DNA in maternal plasma offered the possibility of a non
invasive approach for prenatal diagnosis (Non Invasive Prenatal Diagnosis, NIPD). However,
only a small fraction of total cell-free DNA is of fetal origin, and its study widened only
recently with the development of new technologies, such as digital PCR and Massively Parallel
Sequencing.
Circulating fetal cells (CFC) represent a promising approach, but need further development
before routine implementation To date, clinical applications are limited to Non Invasive
Prenatal Testing for fetal aneuploidy and non invasive detection of fetal-specific genomic
regions, for example fetal sex determination or fetal RHD genotyping, or more recently de
novo mutations that can be suspected after echographic findings, such as achondroplasia. Yet,
NIPD of maternally-inherited monogenic diseases remains challenging, for the fetal allele is
hidden within a large amount of identical maternal sequences. Some publications report
successful NIPD of maternally-inherited monogenic diseases, but only on case reports or small
cohorts, without a standardized protocol and control of statistical risks.
In this study, we aim :
- to develop a new non invasive approach to Prenatal Diagnosis using both direct and
indirect strategy by Massively Parallel Sequencing,
- to identify and characterize CFC.
Methods:
We recently acquired the Chromium™ technology (10XGenomics™). This approach, relying on
microfluidic-based linked-read sequencing, allows direct haplotype phasing from long input
DNA molecules, in this case parental genomic DNA. It is therefore possible to identify the
mutant-linked haplotype for each parent and deduce fetal status with concomitant plasma DNA
analysis.
We plan to include couples at risk of transmitting cystic fibrosis, during genetic counseling
for prenatal diagnosis (PND). Non invasive analysis will be performed concomitantly to
conventional PND, which will be performed on invasive fetal sample. After sequencing, we will
use a new analysis algorithm that allows strict control of statistical risk.
Furthermore, we plan on using the Chromium Single Cell Solution (10XGenomics™) to isolate
CFC. This approach allows analysis of single cell gene expression from thousands cells in a
sample.
Expected results:
In this first study, we wish to include 20 couples in the course of 12 months, which will
represent the largest cohort published to date.
We aim to assess feasibility of this new promising technology of Universal Haplotyping by
linked-read sequencing in the context of NIPD of monogenic diseases, in terms of result
accuracy as well as analysis time and technical cost. This straightforward protocol opens
perspectives for a first-intention non invasive approach of prenatal diagnosis of familial
monogenic diseases.
The Single Cell Solution will also enable us to differentiate the cell types circulating in
maternal blood, and to identify molecular markers to isolate CFC.
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