EncephalopathyNCT03525431
Clinical Utility of Pediatric Whole Exome Sequencing
A study testing Whole Exome Sequencing in people with Encephalopathy and Birth Defect, run by University of California, San Francisco at 4 sites in United States.
Trial summary
The investigator aims to examine the clinical utility of WES, including assessment of a variety of clinical outcomes in undiagnosed pediatric cases. Read more about this study
- Who is it for?
- Ages Up to 25 years
- Conditions the study is for
- Encephalopathy, Birth Defect, Intellectual Disability
- What is being tested?
- Whole Exome Sequencing
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 529 participants
- Where
- 4 sitesUnited States
- Study dates
- 1 Aug 2017to 13 May 2022
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Presenting clinical features suggestive of a genetic etiology, including intellectual disability, seizures, multiple congenital anomalies, metabolic conditions, and neurodegenerative conditions or idiopathic cerebral palsy.
- 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.
Who cannot join
- Prior WES performed for a clinical or research indication
- Lack of phenotypic indication of a likely underlying genetic etiology
- Both biological parents are unavailable.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
UCSF Fresno
Fresno, California, 93701
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609
Zuckerberg San Francisco General Hospital
San Francisco, California, 94110
Benioff Children's Hospital Mission Bay
San Francisco, California, 94158
About this study
Official title: Genomic Sequencing to Aid Diagnosis in Pediatric and Prenatal Practice: Examining Clinical Utility, Ethical Implications, Payer Coverage, and Data Integration in a Diverse Population.
The investigator aims to examine the clinical utility of WES, including assessment of a variety of clinical outcomes in undiagnosed pediatric cases.
Read the 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.
- Conditions
- Encephalopathy, Birth Defect, Intellectual Disability, Multiple Congenital Anomaly, Metabolic Disease, Epilepsy
- Being tested
- Whole Exome Sequencing
- Keywords
- Exome, Sequencing, Clinical Utility, Pediatric, Underrepresented, Underserved
- Medical subject headings
- Brain Diseases, Congenital Abnormalities, Intellectual Disability, Abnormalities, Multiple, Metabolic Diseases, Epilepsy, Cerebral Palsy, Learning Disabilities
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Whole Exome SequencingDiagnostic test
Also called Next Generation 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.
| Study group | Role | What they receive |
|---|---|---|
| Whole Exome Sequencing | Experimental | 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. Receives: Diagnostic Test: Whole Exome Sequencing |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: At the completion of data collection (follow-up visit at 6-12 months after return of results)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2018
- Study start1 Aug 2017
- Primary completion13 May 2022
- Study completion13 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for EncephalopathyStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 529 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- National Human Genome Research Institute (NHGRI)
- Responsible party
- Sponsor
- Investigators
- Pui-Yan Kwok, MD/PhD, Principal investigator, University of California, San FranciscoBarbara Koenig, PhD, Principal investigator, University of California, San FranciscoMary Norton, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03525431
- Sponsor's protocol ID
- 1U01HG009599-01
- Other IDs
- U01HG009599
- Status last verified
- Jun 2023
- First submitted
- 17 Apr 2018
- Last updated
- 18 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.
PubMed 24088041Slavotinek A. Clinical care models in the era of next-generation sequencing. Mol Genet Genomic Med. 2016 May 12;4(3):239-42. doi: 10.1002/mgg3.225. eCollection 2016 May. No abstract available.
PubMed 27247951Rego S, Hoban H, Outram S, Zamora AN, Chen F, Sahin-Hodoglugil N, Anguiano B, Norstad M, Yip T, Lianoglou B, Sparks TN, Norton ME, Koenig BA, Slavotinek AM, Ackerman SL. Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach. Genet Med. 2022 Jun;24(6):1206-1216. doi: 10.1016/j.gim.2022.02.004. Epub 2022 Apr 8.
PubMed 35396980
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genomic Sequencing to Aid Diagnosis in Pediatric and Prenatal Practice: Examining Clinical Utility, Ethical Implications, Payer Coverage, and Data Integration in a Diverse Population.
- ClinicalTrials.gov ID
- NCT03525431
- Acronym / sponsor ID
- 1U01HG009599-01
- Conditions
- Encephalopathy, Birth Defect, Intellectual Disability, Multiple Congenital Anomaly, Metabolic Disease, Epilepsy
- Keywords
- Exome, Sequencing, Clinical Utility, Pediatric, Underrepresented, Underserved
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 529 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- National Human Genome Research Institute (NHGRI)
- Study start
- 1 Aug 2017 (actual)
- Primary completion
- 13 May 2022 (actual)
- Study completion
- 13 May 2022 (actual)
- First posted
- 15 May 2018 (actual)
- Results
- Posted 18 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Whole Exome Sequencing | Experimental | Diagnostic Test: Whole Exome SequencingFollowing 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. |
Who may qualify
- Ages
- Up to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Presenting clinical features suggestive of a genetic etiology, including intellectual disability, seizures, multiple congenital anomalies, metabolic conditions, and neurodegenerative conditions or idiopathic cerebral palsy.
- 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.
Key exclusion criteria (3 listed)
- Prior WES performed for a clinical or research indication
- Lack of phenotypic indication of a likely underlying genetic etiology
- Both biological parents are unavailable.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Whole Exome SequencingAlso: Next Generation SequencingWhole 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. | Diagnostic test | Whole Exome Sequencing |
Primary outcome
Number of Pediatric Patients With a Positive Exome Sequencing Result
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 24088041Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.
- Background: PubMed 27247951Slavotinek A. Clinical care models in the era of next-generation sequencing. Mol Genet Genomic Med. 2016 May 12;4(3):239-42. doi: 10.1002/mgg3.225. eCollection 2016 May. No abstract available.
- Derived from this study: PubMed 35396980Rego S, Hoban H, Outram S, Zamora AN, Chen F, Sahin-Hodoglugil N, Anguiano B, Norstad M, Yip T, Lianoglou B, Sparks TN, Norton ME, Koenig BA, Slavotinek AM, Ackerman SL. Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach. Genet Med. 2022 Jun;24(6):1206-1216. doi: 10.1016/j.gim.2022.02.004. Epub 2022 Apr 8.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pui-Yan Kwok, MD/PhD principal investigator
University of California, San Francisco
Barbara Koenig, PhD principal investigator
University of California, San Francisco
Mary Norton, MD principal investigator
University of California, San Francisco
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Whole Exome Sequencing in people with Encephalopathy and Birth Defect, run by University of California, San Francisco at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Pediatric Patients With a Positive Exome Sequencing Result (time frame: At the completion of data collection (follow-up visit at 6-12 months after return of results)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03525431, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2023.