An interventional study of Whole Exome Sequencing in Encephalopathy, Birth Defect and Intellectual Disability, sponsored by University of California, San Francisco. Completed at 4 sites in United States. Open to participants aged Up to 25 Years. Per ClinicalTrials.gov, last updated 2023-07-18.
Sponsored by University of California, San Francisco · Not applicable, Interventional, and Diagnostic
The investigator aims to examine the clinical utility of WES, including assessment of a variety of clinical outcomes in undiagnosed pediatric cases.
Next-generation sequencing (NGS) is changing the paradigm of clinical genetic testing. Unlike highly focused single-gene tests, NGS allows one to examine gene panels, the exome, and the whole genome. With the broad array of molecular tests now available, ordering physicians face the conundrum of selecting the best diagnostic tool for patients with suspected genetic conditions. Single-gene testing is often most appropriate for conditions with distinctive clinical features and minimal locus heterogeneity. NGS-based gene panel testing, which can be complemented with chromosomal microarray analysis (CMA) and other ancillary methods, provides a comprehensive and feasible approach for well documented but genetically heterogeneous disorders. Whole exome sequencing (WES) and whole genome sequencing (WGS) have the advantage of enabling parallel interrogation of most of the genes in the human genome. To some, WES is preferable to previously used methods due to higher diagnostic yield, shorter time to diagnosis, and improved cost-efficiency.
The ability to survey the exome opens up both new opportunities and new challenges. For example, all coding regions of known genes must be analyzed when applying WES to undiagnosed cases with unclear inheritance patterns. Current limitations on variant interpretation capabilities and clinical validity raise questions about the clinical utility of WES as either a stand-alone or a first-choice diagnostic test. Additional challenges include pre- and post-test counseling with appropriate and robust informed consent, bioinformatics analysis setup and validation, variant interpretation and classification, the need for policies and protocols concerning the discovery and reporting of secondary findings unrelated to the presenting indication, a requirement for validation of WES results, assurance of conformation to quality control standards, data storage and accessibility, and reimbursement issues.
Introducing WES into pediatric clinical care of underrepresented populations raises additional issues and considerations of payment coverage, access, and standards of care. Beyond the sheer complexity of the test and its results, clinicians and health systems must address numerous considerations, including: private and public insurance coverage; language and culture differences and their implications for genetic counseling and clinician-patient relationships; ability to access follow-up testing and clinical care; and ability to access appropriate treatment and services. These issues and others will affect not only patients' decision-making regarding WES, but also their post-test needs for patient follow up. The importance of systematically assessing the clinical utility of NGS is critical for determining in which clinical and health care contexts WES will be useful and for commencing research on these considerations.
502 studies on the registry are indexed under Brain Diseases; 141 are open to participants now.
This study's enrollment of 529 is above the median of 66 across 339 interventional studies indexed under Brain Diseases.
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Even though this study is for pediatric patients, maximum age limit was increased to 25, if patients fulfilling the above criteria were being followed by Pediatrics Department since they were younger than 18.
Exclusion Criteria:
Following consent and collection of standardized phenotypic data, probands and biological parents will undergo WES with variant analysis conducted utilizing primary gene lists based on referring clinical indication. After results provision and follow up 6-12 months later, clinical utility will be assessed in those with a positive result (pathogenic or likely pathogenic variant) and those with negative results (no variant returned or a VUS) using specific outcomes at each site to examine effectiveness for both the child and family.
Diagnostic Test: Whole Exome Sequencing
Whole Exome Sequencing is a form of Next Generation Sequencing allowing investigators to assess the coding regions of many thousands of genes to find variants implicated in disease.
Also known as: Next Generation Sequencing
Number of Pediatric Patients With a Positive Exome Sequencing Result
Number of pediatric patients with a diagnostic result among all patients where exome was performed. A positive exome sequencing result means the identification of a pathogenic or likely pathogenic gene variant to explain the child's condition. The definition of pediatric was expanded to include participants over the age of 18 if they were being followed by UCSF pediatrics department if they were patients at the pediatrics department before they were 18 years old.
Time frame: At the completion of data collection (follow-up visit at 6-12 months after return of results)
We recruited pediatric patients to this study. We aimed to reach 800 pediatric cases in the beginning of the study, and we completed 529 cases at the end.
| Milestone | Whole Exome Sequencing |
|---|---|
| Started | 529 |
| Completed | 529 |
| Not completed | 0 |
Number of pediatric patients with a diagnostic result among all patients where exome was performed. A positive exome sequencing result means the identification of a pathogenic or likely pathogenic gene variant to explain the child's condition. The definition of pediatric was expanded to include participants over the age of 18 if they were being followed by UCSF pediatrics department if they were patients at the pediatrics department before they were 18 years old.
| Participants | Whole Exome Sequencing |
|---|---|
| Number of Pediatric Patients With a Positive Exome Sequencing Result | 142 |
Collected over Each patient was followed for 6-9 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Whole Exome Sequencing | 0/529 (0%) | 0/529 (0%) | 0/529 (0%) |
| Age, Categorical(Participants) | Whole Exome Sequencing |
|---|---|
| <=18 years | 525 |
| Between 18 and 65 years | 4 |
| >=65 years | 0 |
| Age, Continuous(Years) | Whole Exome Sequencing |
|---|---|
| Median | 5.0 (0 to 25) |
| Sex: Female, Male(Participants) | Whole Exome Sequencing |
|---|---|
| Female | 239 |
| Male | 290 |
| Race/Ethnicity, Customized(Participants) | Whole Exome Sequencing |
|---|---|
| American Indian, Native American, Alaska Native | 5 |
| Asian | 45 |
| Black/African American | 19 |
| Native Hawaiian, Pacific Islander | 5 |
| White/European American | 99 |
| Middle Eastern/North African | 22 |
| Hispanic/Latino(a) | 226 |
| More than one | 40 |
| Unknown/none of these fully describe me | 68 |
| Region of Enrollment(participants) | Whole Exome Sequencing |
|---|---|
| United States | 529 |
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This study is completed, as verified in Jun 2023. You cannot join it, but the record below documents what was studied.
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