Prospective Study to Assess Medical Performance of Optical Mapping and Long Read Sequencing in Detecting Numerical and Structural Chromosome Abnormalities
NCT ID: NCT05290051
Last Updated: 2024-12-16
Study Results
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Basic Information
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RECRUITING
NA
400 participants
INTERVENTIONAL
2022-09-26
2026-06-26
Brief Summary
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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.
Detailed Description
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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 14 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®).
Conditions
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Study Design
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NA
SINGLE_GROUP
DIAGNOSTIC
NONE
Study Groups
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Patients referred for cytogenetic analysis
Analysis of patient DNA with Optical Genome Mapping (Bionano®) and long read Sequencing (Nanopore®) in search for chromosome abnormalities (aneuploidies and SV)
Optical Genome Mapping (Bionano®)
Search for chromosome abnormalities through alteration of the optical map of the genome compared to reference genome using the Bionano® 's pipeline.
Longread sequencing (Nanopore®)
Search for chromosome abnormalities from the sequencing data obtain from high molecular weight DNA molecules using dedicated analysis pipeline.
Interventions
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Optical Genome Mapping (Bionano®)
Search for chromosome abnormalities through alteration of the optical map of the genome compared to reference genome using the Bionano® 's pipeline.
Longread sequencing (Nanopore®)
Search for chromosome abnormalities from the sequencing data obtain from high molecular weight DNA molecules using dedicated analysis pipeline.
Eligibility Criteria
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Inclusion Criteria
* ID in a context of perinatal suffering (e.g. hypoxia during labor)
* Children born to non-native French-speaking parents in case of speech/language retardation
* Obstructive azoospermia
* Children under 5kg or whenever blood sampling cannot meet the required volume.
* Missing or wrong blood collection tube
* Insufficient blood volume
* Missing or incomplete consent to research (e.g. only one parental consent for a child)
ALL
No
Sponsors
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CHU Rennes - Hopital Pontchaillou
OTHER
APHP
OTHER
CHU de Rouen - Accueil
OTHER
University Hospital, Strasbourg
OTHER
Université Montpellier
OTHER
University Hospital, Clermont-Ferrand
OTHER
CHU de Reims
OTHER
APHM
UNKNOWN
Hospices Civils de Lyon
OTHER
Institut National de la Santé Et de la Recherche Médicale, France
OTHER_GOV
Responsible Party
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Locations
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Cochin APHP
Paris, , France
Countries
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Central Contacts
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Facility Contacts
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Jean Michel DUPONT, Dr
Role: primary
Other Identifiers
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C21-35
Identifier Type: -
Identifier Source: org_study_id