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

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.

Study Overview

• Status: Unknown
• Conditions: Developmental Disorders
• Intervention / Treatment: Genetic: genome-wide analyses; Genetic: Search for de novo mutations in paternal sperm samples

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: François LECOQUIERRE, MD; Phone Number: 8858 +3323288; Email: francois.lecoquierre@chu-rouen.fr
• Study Contact Backup: Name: Julien BLOT; Phone Number: +3323288; Email: julien.blot@chu-rouen.fr

Study Locations

• France
  • Rouen, France
    • ROUEN university hospital
    • Contact: François LECOQUIERRE, MD
    • Sub-Investigator: Gael NICOLAS, MD

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of the patient's de novo mutations detectable in the father's sperm	Day 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of patients for whom molecular diagnosis has been obtained (cause of developmental disability identified) ≥1	Day 1

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: François LECOQUIERRE, MD, ROUEN university hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): October 1, 2020
• Primary Completion (ANTICIPATED): October 1, 2022
• Study Completion (ANTICIPATED): October 1, 2022

Study Registration Dates

• First Submitted: September 21, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (ACTUAL): September 25, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 25, 2020
• Last Update Submitted That Met QC Criteria: September 21, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease Attributes; Neurodevelopmental Disorders; Recurrence; Developmental Disabilities
• Other Study ID Numbers: 2019/0401/HP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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