Genetic DiseaseReACNCT04575350
Reinterpretation of CNV With Unknown Significance: a 5-year Retrospective Analysis
An observational study of Genetic Disease and CNV, run by Central Hospital, Nancy, France at 1 site in France.
Trial summary
We aim to assess the usefulness of systematic reinterpretation of CNV of unknown significance. To investigate this question we will study all CNV of unknown significance detected between 2010 and 2017. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Genetic Disease, CNV, Genetic Counseling
- What is being tested?
- reinterpretation of CNV
- How many people
- 282 participants
- Where
- 1 siteFrance
- Study dates
- 1 Jan 2019to 1 Jun 2020
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: General population
Who may be able to join
- Signed consent for array-CGH (authorization for the conservation of a biological sample and its subsequent use to continue investigations);
- array-CGHcarried out at the genetics laboratory in Nancy between 1st January 2010 and 31th December 2017 (considering the date of validation of the report);
- Identification of variations of unknown clinical significance.
Who cannot join
- none
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Intérêt de la réinterprétation Des CNV de Signification Inconnue Mis en évidence Par ACPA
We aim to assess the usefulness of systematic reinterpretation of CNV of unknown significance. To investigate this question we will study all CNV of unknown significance detected between 2010 and 2017.
Read the detailed description
Array-CGH is a front-line technique in many genetic indications in both prenatal and postnatal settings. It allows the detection of chromosomal rearrangements (duplication or deletion for example) in routine. The interpretation and classification of these copy number variations or CNVs is essential but complex. It requires a systematic and methodical analysis of the variation in the context of the scientific literature. When these revisions do not meet either pathogenicity or benignity criteria, they are referred to as variation of unknown significance (or VUS). They account for a significant proportion of the revisions up to 75% (Palmer et al., 2013).
The detection of VUS does not, in most cases, allow for a diagnosis and often requires the use of other, costly techniques. The human impact may also be significant in the absence of possible genetic counselling (e.g. in the context of a future pregnancy). Reanalysis of an VUS is of major interest for at least two reasons : (1) the first, if it is classified as benign, makes it possible to close the investigation of the variant, to consider other leads without ulterior motives, and to reassure the patient about the absence of pathogenicity of the variant. (2) if the VUS is ultimately pathogenic, this makes it possible to name the disease for the patient, to specify genetic counselling, to avoid further long and costly investigation and possibly to propose treatment.
Currently, VUS can be reanalysed by the laboratory at the request of the prescribing physician or possibly another physician. However, no systematic reanalysis procedure is currently in place.
Although these variations of unknown meanings are frequent and represent an important issue, to our knowledge, no systematic database study has been carried out. Some similar work has nevertheless been carried out over a shorter period or on an ad hoc basis, showing an interest in this type of approach (Palmer et al., 2014).
Indeed, it seems essential to determine the interest of reanalysing such variations in several modes: diagnostic, economic and human.
- Conditions
- Genetic Disease, CNV, Genetic Counseling, Array CGH
- Being tested
- reinterpretation of CNV
- Medical subject headings
- Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
reinterpretation of CNVGenetic
Reinterpretation of CNV of unknown significance
| Study group | Role | What they receive |
|---|---|---|
| Cohort | no intervention. Receives: Genetic: reinterpretation of CNV |
What is being measured
The primary outcome is the main question the study is designed to answer.
Define the overall rate and per year of reclassification of CNVs after systematic analysis of all those identified as VUS between 2010 and 2016.
The proportion of pathogenic variants will correspond to the percentage of pathogenic variants among all reclassified variants.
Measured: between july 2019 and november 2019
Secondary outcomes (5)
Among the reclassified CNVs, define the proportion of pathogenic variants ;
The proportion of pathogenic variants will correspond to the percentage of pathogenic variants among all reclassified variants.
Measured: between july 2019 and november 2019
Among the CNVs reclassified as pathogens, define the proportion of new diagnoses ;
The proportion of new diagnoses corresponds to the proportion of patients for whom the pathogenicity is related to the pathology among all resolved pathogenic variants.
Measured: between july 2019 and november 2019
Compare the rate of reclassification of CNVs by type (deletion/duplication)
The type of reclassification is defined either by deletion or by chromosomal duplication
Measured: between july 2019 and november 2019
Compare the size of the CNV according to the type of reclassification of the variant.
in bp
Measured: between july 2019 and november 2019
Compare the reclassification rate by type of disease.
The following types of conditions will be considered: prenatal/postnatal; intellectual disability or neurodevelopmental disorder/malformation/other.
Measured: between july 2019 and november 2019
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2020
- Study start1 Jan 2019
- Primary completion1 Jun 2020
- Study completion1 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Genetic DiseaseStudies of the same condition, open and under way.
- More trials run by Central Hospital, Nancy, FranceThe sponsor's other registered studies.
- 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
- 282 participants (actual)
Sponsor and investigators
- Lead sponsor
- Central Hospital, Nancy, France
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Laetitia LAMBERT, Central Hospital, Nancy, France
- Investigators
- Lambert Laëtitia, MD, PhD, Principal investigator, CHRU Nancy, Lorraine University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04575350
- Sponsor's protocol ID
- ReAC
- Acronym
- ReAC
- Status last verified
- Sep 2020
- First submitted
- 29 Sep 2020
- Last updated
- 5 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Palmer E, Speirs H, Taylor PJ, Mullan G, Turner G, Einfeld S, Tonge B, Mowat D. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet A. 2014 Feb;164A(2):377-85. doi: 10.1002/ajmg.a.36279. Epub 2013 Dec 5.
PubMed 24311194Ravel JM, Renaud M, Muller J, Becker A, Renard E, Remen T, Lefort G, Dexheimer M, Jonveaux P, Leheup B, Bonnet C, Lambert L. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome Med. 2023 May 23;15(1):39. doi: 10.1186/s13073-023-01191-6.
PubMed 37221613
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intérêt de la réinterprétation Des CNV de Signification Inconnue Mis en évidence Par ACPA
- ClinicalTrials.gov ID
- NCT04575350
- Acronym / sponsor ID
- ReAC / ReAC
- Conditions
- Genetic Disease, CNV, Genetic Counseling, Array CGH
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 282 participants (actual)
- Lead sponsor
- Central Hospital, Nancy, FranceUniversity, hospital or other
- Study start
- 1 Jan 2019 (actual)
- Primary completion
- 1 Jun 2020 (actual)
- Study completion
- 1 Jun 2020 (actual)
- First posted
- 5 Oct 2020 (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.
We aim to assess the usefulness of systematic reinterpretation of CNV of unknown significance. To investigate this question we will study all CNV of unknown significance detected between 2010 and 2017.
Detailed description
Array-CGH is a front-line technique in many genetic indications in both prenatal and postnatal settings. It allows the detection of chromosomal rearrangements (duplication or deletion for example) in routine. The interpretation and classification of these copy number variations or CNVs is essential but complex. It requires a systematic and methodical analysis of the variation in the context of the scientific literature. When these revisions do not meet either pathogenicity or benignity criteria, they are referred to as variation of unknown significance (or VUS). They account for a significant proportion of the revisions up to 75% (Palmer et al., 2013).
The detection of VUS does not, in most cases, allow for a diagnosis and often requires the use of other, costly techniques. The human impact may also be significant in the absence of possible genetic counselling (e.g. in the context of a future pregnancy). Reanalysis of an VUS is of major interest for at least two reasons : (1) the first, if it is classified as benign, makes it possible to close the investigation of the variant, to consider other leads without ulterior motives, and to reassure the patient about the absence of pathogenicity of the variant. (2) if the VUS is ultimately pathogenic, this makes it possible to name the disease for the patient, to specify genetic counselling, to avoid further long and costly investigation and possibly to propose treatment.
Currently, VUS can be reanalysed by the laboratory at the request of the prescribing physician or possibly another physician. However, no systematic reanalysis procedure is currently in place.
Although these variations of unknown meanings are frequent and represent an important issue, to our knowledge, no systematic database study has been carried out. Some similar work has nevertheless been carried out over a shorter period or on an ad hoc basis, showing an interest in this type of approach (Palmer et al., 2014).
Indeed, it seems essential to determine the interest of reanalysing such variations in several modes: diagnostic, economic and human.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cohort | – | Genetic: reinterpretation of CNVno intervention. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- General population
Key inclusion criteria (3 listed)
- Signed consent for array-CGH (authorization for the conservation of a biological sample and its subsequent use to continue investigations);
- array-CGHcarried out at the genetics laboratory in Nancy between 1st January 2010 and 31th December 2017 (considering the date of validation of the report);
- Identification of variations of unknown clinical significance.
Key exclusion criteria (1 listed)
- none
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 |
|---|---|---|
| reinterpretation of CNVReinterpretation of CNV of unknown significance | Genetic | Cohort |
Primary outcome
Define the overall rate and per year of reclassification of CNVs after systematic analysis of all those identified as VUS between 2010 and 2016.
Time frame: between july 2019 and november 2019
The proportion of pathogenic variants will correspond to the percentage of pathogenic variants among all reclassified variants.
5 secondary outcomes
Among the reclassified CNVs, define the proportion of pathogenic variants ;
Time frame: between july 2019 and november 2019
Among the CNVs reclassified as pathogens, define the proportion of new diagnoses ;
Time frame: between july 2019 and november 2019
Compare the rate of reclassification of CNVs by type (deletion/duplication)
Time frame: between july 2019 and november 2019
Compare the size of the CNV according to the type of reclassification of the variant.
Time frame: between july 2019 and november 2019
Compare the reclassification rate by type of disease.
Time frame: between july 2019 and november 2019
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2020.
- Background: PubMed 24311194Palmer E, Speirs H, Taylor PJ, Mullan G, Turner G, Einfeld S, Tonge B, Mowat D. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet A. 2014 Feb;164A(2):377-85. doi: 10.1002/ajmg.a.36279. Epub 2013 Dec 5.
- Derived from this study: PubMed 37221613Ravel JM, Renaud M, Muller J, Becker A, Renard E, Remen T, Lefort G, Dexheimer M, Jonveaux P, Leheup B, Bonnet C, Lambert L. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome Med. 2023 May 23;15(1):39. doi: 10.1186/s13073-023-01191-6.
- Individual participant dataSharing planned: Undecided
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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.
Lambert Laëtitia, MD, PhD principal investigator
CHRU Nancy, Lorraine University
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 Genetic Disease and CNV, run by Central Hospital, Nancy, France 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 3 inclusion and 1 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: finished, as of the sponsor's last update on 5 Oct 2020. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Define the overall rate and per year of reclassification of CNVs after systematic analysis of all those identified as VUS between 2010 and 2016. (time frame: between july 2019 and november 2019). 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 NCT04575350, which also lists 2 linked publications.
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 5 Oct 2020.