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

NCT04564235 | Completed

• 1 other identifier: 2019/0401/HP
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

1. 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. 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. 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

Outcome Measures

Primary Outcomes (1)

• Proportion of the patient's de novo mutations detectable in the father's sperm

  Day 1

Secondary Outcomes (1)

• Number of patients for whom molecular diagnosis has been obtained (cause of developmental disability identified) ≥1

  Day 1

Study Arms (1)

Indication for a genome-wide analysis in the proband

EXPERIMENTAL

Genetic: genome-wide analyses; Genetic: Search for de novo mutations in paternal sperm samples

Interventions

genome-wide analyses GENETIC

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

Indication for a genome-wide analysis in the proband

Search for de novo mutations in paternal sperm samples GENETIC

Sperm analysis will be done in paternal samples

Indication for a genome-wide analysis in the proband

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Rouen: lead

Study Sites (1)

Rouen University Hospital

Rouen, France

Location

Related Publications (2)

• Lecoquierre F, Drouot N, Coutant S, Quenez O, Fourneaux S, Jumeau F, Rives N, Charbonnier F, Derambure C, Boland A, Olaso R, Meyer V, Deleuze JF, Goldenberg A, Guerrot AM, Charbonnier C, Nicolas G. Parental germline mosaicism in genome-wide phased de novo variants: Recurrence risk assessment and implications for precision genetic counselling. PLoS Genet. 2025 Mar 31;21(3):e1011651. doi: 10.1371/journal.pgen.1011651. eCollection 2025 Mar.

  PMID: 40163539 RESULT

• Lecoquierre F, Quenez O, Fourneaux S, Coutant S, Vezain M, Rolain M, Drouot N, Boland A, Olaso R, Meyer V, Deleuze JF, Dabbagh D, Gilles I, Gayet C, Saugier-Veber P, Goldenberg A, Guerrot AM, Nicolas G. High diagnostic potential of short and long read genome sequencing with transcriptome analysis in exome-negative developmental disorders. Hum Genet. 2023 Jun;142(6):773-783. doi: 10.1007/s00439-023-02553-1. Epub 2023 Apr 19.

  PMID: 37076692 RESULT

MeSH Terms

Conditions

Developmental Disabilities

Condition Hierarchy (Ancestors)

Neurodevelopmental Disorders; Mental Disorders

Study Officials

• François LECOQUIERRE, MD

  University Hospital, Rouen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2020
• First Posted: September 25, 2020
• Study Start: February 24, 2021
• Primary Completion: December 12, 2022
• Study Completion: December 12, 2022
• Last Updated: April 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)