Birth Defect, Cerebral Palsy, Developmental Defect, Developmental Delay, Encephalopathy, Epilepsy, Intellectual Disability, Metabolic Disease, Multiple Congenital Anomaly, Neuro-Degenerative Disease
Conditions
Keywords
Exome, Sequencing, Clinical Utility, Pediatric, Underrepresented, Underserved
Brief summary
The investigator aims to examine the clinical utility of WES, including assessment of a variety of clinical outcomes in undiagnosed pediatric cases.
Detailed description
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.
Interventions
DIAGNOSTIC_TESTWhole 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.
Sponsors
National Human Genome Research Institute (NHGRI)
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Presenting clinical features suggestive of a genetic etiology, including intellectual disability, seizures, multiple congenital anomalies, metabolic conditions, and neurodegenerative conditions or idiopathic cerebral palsy. 2. A minimum of one biological parent is available and willing to provide a specimen for WES, with a preference for two available parents. At least one parent consenting to WES of the child. 4\. Pediatric patients must have had at least one prior genetics appointment or evaluation 5. Pediatric patients may have had a single nucleotide polymorphism (SNP) array or oligonucleotide array that did not provide a diagnosis. 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
1. Prior WES performed for a clinical or research indication 2. Lack of phenotypic indication of a likely underlying genetic etiology 3. Both biological parents are unavailable.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pediatric Patients With a Positive Exome Sequencing Result | At the completion of data collection (follow-up visit at 6-12 months after return of results) | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
This is an exploratory study to define the diagnostic yield of exome sequencing in this pediatric population. All participants were offered the same test and received the same study procedures. There are no arms in this study.
Participants by arm
| Arm | Count |
|---|---|
| Whole Exome Sequencing 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 months later, diagnostic yield will be assessed as a measure of clinical utility. Those with a positive result (pathogenic or likely pathogenic variant) divided by the total number of cases sequenced will give the diagnostic yield. The assessment will be per pediatric case (proband), meaning, genomic data from biological parents and occasionally from siblings will be used to support the diagnosis for the proband.
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. | 529 |
| Total | 529 |
Baseline characteristics
| Characteristic | Whole Exome Sequencing |
|---|---|
| Age, Categorical <=18 years | 525 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 5.0 Years |
| Race/Ethnicity, Customized American Indian, Native American, Alaska Native | 5 Participants |
| Race/Ethnicity, Customized Asian | 45 Participants |
| Race/Ethnicity, Customized Black/African American | 19 Participants |
| Race/Ethnicity, Customized Hispanic/Latino(a) | 226 Participants |
| Race/Ethnicity, Customized Middle Eastern/North African | 22 Participants |
| Race/Ethnicity, Customized More than one | 40 Participants |
| Race/Ethnicity, Customized Native Hawaiian, Pacific Islander | 5 Participants |
| Race/Ethnicity, Customized Unknown/none of these fully describe me | 68 Participants |
| Race/Ethnicity, Customized White/European American | 99 Participants |
| Region of Enrollment United States | 529 participants |
| Sex: Female, Male Female | 239 Participants |
| Sex: Female, Male Male | 290 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 529 |
| other Total, other adverse events | 0 / 529 |
| serious Total, serious adverse events | 0 / 529 |
Outcome results
Primary
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)
Population: 529 Probands total were enrolled in the study, 525 pediatric participants, and 4 were over the age of 18.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole Exome Sequencing | Number of Pediatric Patients With a Positive Exome Sequencing Result | 142 Participants |