Reinterpretation of CNV With Unknown Significance: a 5-year Retrospective Analysis (ReAC)

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.

Study Overview

• Status: Completed
• Conditions: Genetic Disease; CNV; Genetic Counseling; Array CGH
• Intervention / Treatment: Genetic: reinterpretation of CNV

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 Type: Observational
• Enrollment (Actual): 282

Contacts and Locations

Study Locations

• France
  • Nancy, France
    • Lorraine University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

General population

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• none

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort; no intervention.	Genetic: reinterpretation of CNV; Reinterpretation of CNV of unknown significance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	between july 2019 and november 2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	between july 2019 and november 2019
Compare the size of the CNV according to the type of reclassification of the variant.	in bp	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.	between july 2019 and november 2019

Collaborators and Investigators

• Sponsor: Central Hospital, Nancy, France
• Investigators: Principal Investigator: Lambert Laëtitia, MD, PhD, CHRU Nancy, Lorraine University

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2019
• Primary Completion (ACTUAL): June 1, 2020
• Study Completion (ACTUAL): June 1, 2020

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: September 29, 2020
• First Posted (ACTUAL): October 5, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 5, 2020
• Last Update Submitted That Met QC Criteria: September 29, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn
• Other Study ID Numbers: ReAC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No