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Clinical Utility of Pediatric Whole Exome Sequencing

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03525431
Recruitment Status : Active, not recruiting
First Posted : May 15, 2018
Last Update Posted : August 9, 2021
National Human Genome Research Institute (NHGRI)
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
The investigator aims to examine the clinical utility of WES, including assessment of a variety of clinical outcomes in undiagnosed pediatric cases.

Condition or disease Intervention/treatment Phase
Encephalopathy Birth Defect Intellectual Disability Multiple Congenital Anomaly Metabolic Disease Epilepsy Neuro-Degenerative Disease Cerebral Palsy Developmental Delay Developmental Defect Diagnostic Test: Whole Exome Sequencing Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
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.
Actual Study Start Date : August 1, 2017
Actual Primary Completion Date : May 31, 2021
Estimated Study Completion Date : November 30, 2021

Arm Intervention/treatment
Experimental: 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 6-12 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.
Other Name: Next Generation Sequencing

Primary Outcome Measures :
  1. Clinical Utility of WES [ Time Frame: At the completion of data collection (follow-up visit at 6-12 months after return of results) ]
    Our outcome will be an assessment of clinical utility in patients that receive a positive (pathogenic or likely pathogenic) result. Clinical utility will be measured with a quantitative score based on changes in medical care, such as starting or ceasing medications or medical surveillance, investigations, other forms of treatments and specialist visits and prognosis.

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts 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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03525431

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United States, California
UCSF Fresno
Fresno, California, United States, 93701
UCSF Benioff Children's Hospital Oakland
Oakland, California, United States, 94609
Zuckerberg San Francisco General Hospital
San Francisco, California, United States, 94110
Benioff Children's Hospital Mission Bay
San Francisco, California, United States, 94158
Sponsors and Collaborators
University of California, San Francisco
National Human Genome Research Institute (NHGRI)
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Principal Investigator: Pui-Yan Kwok, MD/PhD University of California, San Francisco
Principal Investigator: Barbara Koenig, PhD University of California, San Francisco
Principal Investigator: Mary Norton, MD University of California, San Francisco
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Responsible Party: University of California, San Francisco Identifier: NCT03525431    
Other Study ID Numbers: 1U01HG009599-01 ( U.S. NIH Grant/Contract )
U01HG009599 ( U.S. NIH Grant/Contract )
First Posted: May 15, 2018    Key Record Dates
Last Update Posted: August 9, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by University of California, San Francisco:
Clinical Utility
Additional relevant MeSH terms:
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Cerebral Palsy
Brain Diseases
Intellectual Disability
Neurodegenerative Diseases
Congenital Abnormalities
Abnormalities, Multiple
Metabolic Diseases
Central Nervous System Diseases
Nervous System Diseases
Brain Damage, Chronic
Neurobehavioral Manifestations
Neurologic Manifestations
Neurodevelopmental Disorders
Mental Disorders