Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05290051 |
| Other study ID # |
C21-35 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 2022 |
| Est. completion date |
April 2024 |
Study information
| Verified date |
March 2022 |
| Source |
Institut National de la Santé Et de la Recherche Médicale, France |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Chromosomal aberrations are major causes of developmental disorders (Intellectual disability
(ID), multiple congenital anomalies (MCA), autism spectrum disorders (ASD)) as well as
reproductive disorders (RD) in particular gametogenesis defects and recurrent miscarriages.
Current first tier genetic investigations for chromosome analysis in clinical settings
include karyotyping in case of RD (5 ~ 10% diagnosis rate) and chromosomal microarrays (CMA)
in case of ID/MM (10 ~ 20% diagnosis rate). However, both assays show significant drawbacks,
e.g. low resolution for karyotyping and inability to detect balanced structural rearrangement
for CMA.
Optical genome mapping and long read genome sequencing are emerging technologies that offer
new opportunities to overcome these limitations and allow for a higher resolution chromosome
analysis.
This project aims at assessing the performance of optical mapping and long read whole genome
sequencing compared to current gold standard cytogenetics methods in a prospective study. The
investigator will evaluate their ability to become the all-in-one methodology for genomic
analysis that could replace both karyotype and CMA and their added-value compared to these
latter by uncovering new diagnoses.
Description:
Chromosome aberrations are found in up to 1% of the general population. Structural
aberrations, either balanced (3.6‰) or unbalanced (0.9‰), represent a third of them. Most
(but not all) unbalanced anomalies are associated with a relevant phenotype, while most (but
not all) balanced rearrangements have no consequence on the phenotype except possible
reproductive disorders. Indeed, the prevalence of the latter among infertile individuals is
ten times higher than in the fertile population. Moreover, 6% - 27% of apparently balanced
rearrangements can lead to developmental disorders through various mechanisms.
First tier chromosome analysis methods, karyotype and chromosomal microarray analysis (CMA),
are hampered either by a low resolution (karyotype) or by their inability to detect balanced
rearrangements (CMA). However, karyotyping is still the gold standard analysis in case of
reproductive disorders (RD) and recurrent miscarriages because of the high prevalence of
aneuploidies (mainly sex chromosome aneuploidies, i.e. 45,X or 47,XXY) or balanced structural
abnormalities.
According to a French national annual survey carried out by the Agence de la Biomedecine, the
diagnostic yield is ~5%-10% for karyotyping in RD and ~15-20% for CMA in ID/MCA. Hence, many
patients remain without a molecular diagnosis of their condition after these first tier
studies. Whole exome sequencing and now whole genome sequencing have been shown to be able to
rise the diagnostic yield to up to 50-60% in ID patients. However, current short read
sequencing methods fall short to providing robust data for structural variation (SV)
detection, because of the inability of bioinformatic tools to map correctly the sequences due
to the high proportion of homologous sequences at SV breakpoints. New emerging methodologies
based on long DNA fragments are now available and may provide a way to circumvent current
limitations: long read sequencing (lrNGS) and optical genome mapping (OGM) :
OGM has been developed by Bionano Genomics and combines microfluidic and high-resolution
microscopy to offer an imaging of long, high molecular weight, DNA molecules (up to more than
1Mb) labelled with specific sequence tags. From these images, a de novo assembly of any
patient's genome can be performed and compared to a reference genome map to unravel all kind
of structural rearrangements with a resolution that is 100 to 1000 times higher than with
karyotyping. A second pipeline based on coverage in each region allows for the detection of
large CNVs and aneuploidies.
lrNGS of long DNA fragments (several kb) reduces short read sequencing based assembly issues
due to repetitive sequences, and allow for detection of all mutations, from SNVs to SVs and
CNVs. Due to the large size of fragment inserts, less false positive are expected for SV
calling than observed with short read or linked-read sequencing. Although bioinformatics
pipelines are improving, prospective detection of large SV/SNV remains challenging, with a
very high rate of false positives and false negatives. Furthermore, no study has been
conducted to test prospectively the feasibility and medical efficiency of using long read
sequencing as a first-tier all-in-one test for SV and CNV identification.
Primary Objective The main objective of this prospective study is to compare the diagnosis
rate of OGM (Bionano®) and lrNGS (Nanopore®) to the one of standard-of-care technologies,
e.g. karyotyping for patients presenting with reproductive disorders (primary amenorrhea,
premature ovarian insufficiency, severe oligozoospermia, azoospermia) or CMA in case of
developmental disorders (ID/MCA).
Secondary Objectives Refine the data on the incidence and type of chromosomal aberrations in
the different clinical categories of patients Assess the limits of Bionano® and Nanopore®
Assess the impact of enhanced detection of subchromosomal anomalies by Bionano® or Nanopore®
on the medical care of the patient Compare the cost-effectiveness of both approaches
Study type This is a national multicentric prospective cohort study involving 11 French
certified constitutional cytogenetic centers. The same patients will be offered genome wide
analysis using standard techniques (Karyotyping or CMA according to the reason for referral)
and two new genome wide analysis methods, OGM (Bionano®) and lrNGS (Nanopore®).
