NIPD on cffDNA for Triplet Repeat Diseases

January 4, 2021 updated by: University Hospital, Montpellier

Comparison of Two NGS Phasing Techniques of Parental Haplotypes for NIPD of Triplet Expansion Diseases

The purprose of this study is to develop and validate an analytical NIPD test for triplet repeat disesases by NGS analysis from maternal blood, searching for the familial mutation in families at risk of having one of the following triplet repeat diseases: Huntington's disease, Myotonic dystrophy, Fragile X syndrome.. A comparison of two 3rd generation long fragment DNA sequencing techniques will be performed. These methods are based of the phasing techniques of parental haplotypes without the proband.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Context:

The ability to sequence fetal cfDNA has led to exciting new developments for the non-invasive genetic diagnosis of monogenic diseases (DPNI_MGR). Various tests are proposed for diseases with predominantly de novo dominant, dominant paternal and some recessive paternal mutations. However, technical difficulties related to the determination of the maternal allelic balance remain, in particular during the phasing of parental haplotypes according to a trio strategy which requires the availability of parental genomic DNAs and at least one healthy or affected child. Moreover 2nd generation sequencers do not allow the haplotyping of alleles carrying dynamic mutations.

Objectives:

This project proposes the validation of a semi-universal DPNI_MGR test applicable to the majority of the genes and mutations involved in DPN requests from phasing of parental haplotypes by 3rd generation long-fragment DNA sequencing techniques coupled with targeted sequencing of free circulating DNA from maternal plasma. This test will be validated using triplet expansion diseases, which are the second indication of DPN at the national level.

Methodology :

Retrospective study of 16 couples at risk of transmitting a disease with triplet expansions (Myotonic dystrophy of Steinert, Huntington's disease, FRAXA, SCA1, 2, 3)

Phase 1 :

  • Determination for 8 pairs of parental haplotypes according to the technique "Nanopore Cas9 Targeted-Sequencing" (nCATS) and validation of the analytical parameters and quality of this method (coverage rate of the regions of interest, error rate, identification of the morbid allele carrying the expansion ...),
  • Comparison of the parental haplotypes obtained in "Nanopore" technique versus those obtained by the "Linked Reads 10xGenomics" technique in these same 8 pairs (the sequencing and phasing data by this 2nd approach are available from a previous study),
  • Evaluation of the concordance of the fetal genotype results obtained during the standard examination (DPN by amniocentesis or choriocentesis) and those obtained with these new approaches of phasing in PNID.

Phase 2:

- Validation of the best performing workflow (efficiency / cost) of phase 1 over 8 additional pairs for a clinical transfer of the approach.

Expected results and prospects:

This study should make it possible to define the best performing test for the DPNI of triplet expansion diseases in accordance with the knowledge of the art and to validate the transfer conditions in clinical practice of the approach (equipment, reagents, cost analysis, analytical validation criteria ....).

The validated workflow should be as universal as possible to secondarily provide national level access to a wide range of rare diseases NIDP by future adjustments of the gene content of the free circulating DNA sequencing panels.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
36

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Montpellier, France, 34295
        • CHU Montpellier

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

1 year and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Retrospective study of 16 couples at risk of transmitting a disease with triplet expansions (Myotonic dystrophy of Steinert, Huntington's disease, FRAXA) Couples undergoing prenatal diagnosis for a monogenic disease caused by dynamic mutation

Description

Inclusion criteria:

  • Couple at risk (based on family history or echographic findings) for one of the following diseases: Huntington's disease, Steinert's myotonic dystrophy, fragile X
  • Written informed consent was obtained for DIACCIMEX study and mentionned "authorization for use for further studies on familial pathology. Indeed, the DNA can be used anonymized for the development of new analyzes of non-invasive prenatal diagnosis".
  • Prenatal diagnosis has been done for the pregnancy during which maternal blood has been collected
  • Couple molecular diagnosis results for one of the following diseases (Huntington's disease, Steinert's myotonic dystrophy, fragile X and spinocerebellar ataxias 1, 2 or 3 ) MUST BE AVAILABLE.

Exclusion criteria:

  • Couple Genomic DNA are unavailable
  • Subjects at risk of transmitting the family disease, but not wishing to know their molecular status
  • Individuals under guardianship by court order

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
16 pregnant women and their spouses
Genetic: Non invasive prenatal diagnosis
Search for the familial mutation involved in DPN requests from phasing of parental haplotypes by 3rd generation long-fragment DNA sequencing techniques coupled with targeted sequencing of free circulating DNA from maternal plasma.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Concordance rate between cell free foetal DNA based genetic
Time Frame: 36 months
t is a qualitative analysis : for each sample of each pregnant women, the presence of absence of a mutation (or morbid haplotype) responsible for a triplet expansion will be determined from maternal blood (Non invasive Pregnancy Diagnosis). the result could be : health fetus, affected fetus or non conclusive result (i.e. the analysis didn't allow to conclude if the fetus would be affected or not) Then, determination of the concordance rate between cell-based genetic non invasive prenatal test and gold standard prenatal test (choriocentesis or amniocentesis). Analysis of the concordance of the prenatal results obtained by our new NIPD (Non-Invasive Prenatal Diagnosis) approach and those blindly obtained during the gold-standard prenatal genetic test will be carried out for each pregnant woman participating in the study
36 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Qualitative process to define the differents steps to analysis of the cell free foetal DNA
Time Frame: 36 months
Qualitative choice : define the most efficiency workflow in term of ratio cost/efficacity between the two kits of long fragment sequencing (simplicity, rapidity, accuracy and cost of the products )
36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Montpellier

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Agence de La Biomédecine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 1, 2020

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2023

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 1, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 4, 2021

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 7, 2021

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 7, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 4, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RECHMPL20_0441

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

NC

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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