Our research team is currently recruiting neonates and young children who meet all of the criteria listed below.
- Complex overt anatomical defects in which either two or more organ systems are affected, or multiple anomalies occur within at least one of the following:
- Central and/or peripheral nervous system
- Cardiac and vascular system
- Craniofacial features and/or skeletal system
- Skeletal muscle
- Visceral organs, such as kidney, liver, pancreas and gut
- No molecular diagnosis at the time of enrollment. This includes normal chromosomes according to karyotype and/or microarray analysis.
- In addition to the affected child, both parents must be willing to participate. We also invite extended family members to enroll in our studies for confirmatory sequencing studies.
- Cases involving a known environmental or maternal confounding factor (e.g., gestational diabetes) will be excluded.
Informed consent for enrollment
If a family meets all Task Force inclusion criteria and is interested in participating in our studies, a Board Certified genetic counselor will serve as the point of contact to the family during the consent process.
Sample and information collection
Following informed consent, we will arrange for collection of either a blood or saliva sample for extraction of DNA. We may also obtain residual DNA samples banked in a clinical laboratory. We will obtain a detailed medical history from the family.
Using the latest next-generation sequencing technologies, we will sequence the exome of the affected child and each of the parents. The exome accounts for the ~2% of the genome that makes up genes, which encode the ~25,000 proteins that make up all cells and tissues of the body. In some instances, we may extend our studies to whole-genome sequencing. We will then analyze the data using current informatics approaches and human genetic variation databases to identify candidate causal variants. We will use traditional Sanger sequencing methodology to confirm variants of interest.
Functional interpretation of candidate DNA changes
In instances when we identify candidate causal variants that have not been reported previously in the scientific literature, or reside in a gene that has not previously been implicated in human genetic disease, we will develop a research model to test variant effect on protein function. Depending on the organ systems affected in the child, we will develop a cell-based, or in vivo (using mice and/or zebrafish) model to test variants in a physiologically relevant manner.
Clinical confirmation of clinically actionable results
The Task Force will report mutational findings that are of immediate clinical relevance to the family’s referring physician in the form of a written report. Results must be confirmed in a CLIA-certified diagnostic laboratory before they may be reported back to the family.
Regular internal review of progress by the Task Force
During monthly standing meetings or ad hoc meetings with referring physicians, the combined expertise of the Task Force is utilized at multiple steps of the process to review:
- Candidate families for enrollment
- Candidate DNA variants for functional testing
- Formal reports to referring physicians
- Re-review of sequencing data every 18 months