Myotonic Dystrophy 1NCT04698551
NIPD on cffDNA for Triplet Repeat Diseases
An observational study of Myotonic Dystrophy 1 and Huntington Disease, run by University Hospital, Montpellier at 1 site in France.
Trial summary
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.. Read more about this study
- Who is it for?
- Ages 18 months and older
- Conditions the study is for
- Myotonic Dystrophy 1, Huntington Disease, Fragile X Syndrome
- What is being tested?
- Non invasive prenatal diagnosis
- How many people
- 36 participants
- Where
- 1 siteFrance
- Study dates
- 1 Sep 2020to 1 Dec 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Myotonic Dystrophy 1, Huntington Disease, Fragile X Syndrome
- Being tested
- Non invasive prenatal diagnosis
- Keywords
- Non Invasive Prenatal Diagnosis (NIPD), Circulating Fetal DNA (CFTC), triplet expansion diseases
- Medical subject headings
- Myotonic Dystrophy, Huntington Disease, Fragile X Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Non invasive prenatal diagnosisGenetic
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.
| Study group | Role | What they receive |
|---|---|---|
| 16 pregnant women and their spouses | 16 pregnant women and their spouses Receives: Genetic: Non invasive prenatal diagnosis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Concordance rate between cell free foetal DNA based genetic
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
Measured: 36 months
Secondary outcomes (1)
Qualitative process to define the differents steps to analysis of the cell free foetal DNA
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 )
Measured: 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2021
- Study start1 Sep 2020
- Primary completion1 Sep 2023 (estimated)
- Study completion1 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Myotonic Dystrophy 1Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 36 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Montpellier
- Sponsor type
- University, hospital or other
- Collaborators
- Agence de La Biomédecine
- Responsible party
- Sponsor
- Investigators
- Marie Claire VINCENT, PhD-PharmaD, Principal investigator, University Hospital, Montpellier
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04698551
- Sponsor's protocol ID
- RECHMPL20_0441
- Status last verified
- Sep 2020
- First submitted
- 1 Sep 2020
- Last updated
- 7 Jan 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: NC
Publications
Liautard-Haag C, Durif G, VanGoethem C, Baux D, Louis A, Cayrefourcq L, Lamairia M, Willems M, Zordan C, Dorian V, Rooryck C, Goizet C, Chaussenot A, Monteil L, Calvas P, Miry C, Favre R, Le Boette E, Fradin M, Roux AF, Cossee M, Koenig M, Alix-Panabiere C, Guissart C, Vincent MC. Noninvasive prenatal diagnosis of genetic diseases induced by triplet repeat expansion by linked read haplotyping and Bayesian approach. Sci Rep. 2022 Jul 6;12(1):11423. doi: 10.1038/s41598-022-15307-2.
PubMed 35794169
Study at a glance
From the registry record, last updated by the sponsor on 7 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Two NGS Phasing Techniques of Parental Haplotypes for NIPD of Triplet Expansion Diseases
- ClinicalTrials.gov ID
- NCT04698551
- Acronym / sponsor ID
- RECHMPL20_0441
- Conditions
- Myotonic Dystrophy 1, Huntington Disease, Fragile X Syndrome
- Keywords
- Non Invasive Prenatal Diagnosis (NIPD), Circulating Fetal DNA (CFTC), triplet expansion diseases
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 36 participants (estimated)
- Lead sponsor
- University Hospital, MontpellierUniversity, hospital or other
- Collaborators
- Agence de La Biomédecine
- Study start
- 1 Sep 2020 (actual)
- Primary completion
- 1 Sep 2023 (estimated)
- Study completion
- 1 Dec 2023 (estimated)
- First posted
- 7 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 16 pregnant women and their spouses | – | Genetic: Non invasive prenatal diagnosis16 pregnant women and their spouses |
Who may qualify
- Ages
- 18 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Non invasive prenatal diagnosisSearch 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. | Genetic | 16 pregnant women and their spouses |
Primary outcome
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
1 secondary outcome
Qualitative process to define the differents steps to analysis of the cell free foetal DNA
Time frame: 36 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jan 2021.
- Derived from this study: PubMed 35794169Liautard-Haag C, Durif G, VanGoethem C, Baux D, Louis A, Cayrefourcq L, Lamairia M, Willems M, Zordan C, Dorian V, Rooryck C, Goizet C, Chaussenot A, Monteil L, Calvas P, Miry C, Favre R, Le Boette E, Fradin M, Roux AF, Cossee M, Koenig M, Alix-Panabiere C, Guissart C, Vincent MC. Noninvasive prenatal diagnosis of genetic diseases induced by triplet repeat expansion by linked read haplotyping and Bayesian approach. Sci Rep. 2022 Jul 6;12(1):11423. doi: 10.1038/s41598-022-15307-2.
- Individual participant dataSharing planned: Undecided. NC
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marie Claire VINCENT, PhD-PharmaD principal investigator
University Hospital, Montpellier
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Myotonic Dystrophy 1 and Huntington Disease, run by University Hospital, Montpellier at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Concordance rate between cell free foetal DNA based genetic (time frame: 36 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04698551, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jan 2021.