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Risk of Recurrence of de Novo Mutations: Research and Quantification of Paternal Germinal Mosaicism by the Combined Use of Genomic Tools (RRMUT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04564235
Recruitment Status : Not yet recruiting
First Posted : September 25, 2020
Last Update Posted : September 25, 2020
Information provided by (Responsible Party):
University Hospital, Rouen

Brief Summary:
  1. Inclusion of 5 families Inclusions will be made by the clinical genetics department of the Rouen University Hospital (monocentric study) and will correspond to trios of parents + child with unexplained developmental abnormalities. The inclusion of patients will be integrated in routine care and will have as immediate benefit for the included families the extensive analysis of the proband and their parents' genomes by short and long read sequencing techniques, which represent the most comprehensive diagnostic tests for developmental diseases, and which are not currently routinely available. Inclusion in clinical genetics by clinicians accustomed to prescribing genome-wide analyses will allow clear and complete information to families. Collection of consents. The trio's DNA will already be available at the molecular genetics laboratory, and a new blood sample may be proposed if necessary. Collection of sperm from the father.
  2. Identification of a large set of de novo mutations. Extraction of blood DNA and sending for sequencing of the complete genome to the National Centre for Research in Human Genomics (CNRGH, Evry), in the framework of a collaboration already initiated. Analysis of the sequencing data thanks to the already existing expertise in Rouen. Identification of about 40-120 de novo mutations per trio. At this stage: interpretation of the variations identified with the secondary objective of identifying the cause of the disease in children. Long read genomes will allow to phase the de novo variants to the paternal or to the maternal haplotype.
  3. Search for de novo mutations in paternal sperm samples. Extraction of spermatic DNA. Design of a sequencing panel targeting the genetic variations identified in the different trios. Preparation of the libraries, targeted high throughput sequencing at great depth thanks to the techniques and equipment already operational. Specific search for the de novo variations identified in the probands (in 2.), with for each evaluation of (i) the presence of the variation in the sperm sample, (ii) the quantity of mosaicism, reflecting the proportion of carrier spermatozoa and therefore the risk of recurrence, (iii) the presence of my variation in the blood sample of both parents in deep sequencing.

Condition or disease Intervention/treatment Phase
Developmental Disorders Genetic: genome-wide analyses Genetic: Search for de novo mutations in paternal sperm samples Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Risk of Recurrence of de Novo Mutations: Research and Quantification of Paternal Germinal Mosaicism by the Combined Use of Genomic Tools
Estimated Study Start Date : October 2020
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Indication for a genome-wide analysis in the proband Genetic: genome-wide analyses
genome-wide analyses will be done in patients and parents (father, mother)

Genetic: Search for de novo mutations in paternal sperm samples
Sperm analysis will be done in paternal samples

Primary Outcome Measures :
  1. Proportion of the patient's de novo mutations detectable in the father's sperm [ Time Frame: Day 1 ]

Secondary Outcome Measures :
  1. Number of patients for whom molecular diagnosis has been obtained (cause of developmental disability identified) ≥1 [ Time Frame: Day 1 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Trio consisting of a child with a developmental disorder and both unaffected parents
  • Absence of etiology after clinical expertise and genetic testing
  • Indication of a genome-wide sequencing analysis
  • Child from spontaneous pregnancy without ovulation stimulation treatment
  • Availability of DNA blood samples
  • Affiliation to a social insurance
  • Patient or patient's legal representative who has read and understood the information letter and has signed the consent form

Exclusion Criteria:

  • Lack of indication for a genome-wide analysis in the proband
  • Etiology of the developmental disorder already identified
  • Proband born after In-Vitro Fertilization
  • Impossibility of non-invasive sperm collection from the father

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04564235

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Contact: François LECOQUIERRE, MD +3323288 ext 8858
Contact: Julien BLOT +3323288

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Rouen University Hospital
Rouen, France
Contact: François LECOQUIERRE, MD         
Sub-Investigator: Gael NICOLAS, MD         
Sub-Investigator: Nathalie RIVES, Pr         
Sponsors and Collaborators
University Hospital, Rouen
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Principal Investigator: François LECOQUIERRE, MD Rouen University Hospital
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Responsible Party: University Hospital, Rouen Identifier: NCT04564235    
Other Study ID Numbers: 2019/0401/HP
First Posted: September 25, 2020    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Developmental Disabilities
Disease Attributes
Pathologic Processes
Neurodevelopmental Disorders
Mental Disorders