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

NCT ID: NCT04564235

Last Updated: 2026-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-24
• Study Completion Date: 2022-12-12

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.

Conditions

Developmental Disorders

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Indication for a genome-wide analysis in the proband

Group Type: EXPERIMENTAL

genome-wide analyses

Intervention Type: GENETIC

genome-wide analyses will be done in patients and parents (father, mother)

Search for de novo mutations in paternal sperm samples

Intervention Type: GENETIC

Sperm analysis will be done in paternal samples

Interventions

genome-wide analyses

genome-wide analyses will be done in patients and parents (father, mother)

Intervention Type: GENETIC

Search for de novo mutations in paternal sperm samples

Sperm analysis will be done in paternal samples

Intervention Type: GENETIC

Eligibility Criteria

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

• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital, Rouen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

François LECOQUIERRE, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Rouen

Locations

Rouen University Hospital

Rouen, , France

Countries

France

Other Identifiers

2019/0401/HP

Identifier Type: -

Identifier Source: org_study_id