Developmental Disorders Clinical Trial
— RRMUTOfficial title:
Risk of Recurrence of de Novo Mutations: Research and Quantification of Paternal Germinal Mosaicism by the Combined Use of Genomic Tools
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.
| Status | Not yet recruiting |
| Enrollment | 5 |
| Est. completion date | October 2022 |
| Est. primary completion date | October 2022 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | N/A and older |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| France | Rouen University Hospital | Rouen |
| Lead Sponsor | Collaborator |
|---|---|
| University Hospital, Rouen |
France,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Proportion of the patient's de novo mutations detectable in the father's sperm | Day 1 | ||
| Secondary | Number of patients for whom molecular diagnosis has been obtained (cause of developmental disability identified) =1 | Day 1 |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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