Official Title
Risk of Recurrence of de Novo Mutations: Research and Quantification of Paternal Germinal Mosaicism by the Combined Use of Genomic Tools
Brief Title
Risk of Recurrence of de Novo Mutations: Research and Quantification of Paternal Germinal Mosaicism by the Combined Use of Genomic Tools
Protocol ID
NCT04564235
Lead Sponsor
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.
Study Period
-
Enrollment Count
5 participants
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
Filters
Developmental Disorders
NA
COMPLETED
CHILD
ADULT
OLDER_ADULT