Clinical Utility of Prenatal Whole Exome Sequencing (PWES)

March 22, 2023 updated by: University of California, San Francisco
The investigator aims to examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes in undiagnosed prenatal cases.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Current clinical standards recommend offering chromosomal microarray (CMA) in the prenatal setting when fetal structural anomalies are detected via prenatal ultrasound. In these cases, clinically relevant copy number variants have been reported in 6.0-9.1% of fetuses with a normal karyotype. However, informed consent processes for prenatal CMA are challenging-particularly in cases with ultrasound anomalies, as parents are absorbing challenging news and under considerable stress. Women have reported being "blindsided" by positive CMA results, or feeling that these results were "toxic information"-information they wished they did not have, particularly in cases of uncertain genetic information or uninterpretable variants. Nonetheless, in that same study women who were referred for CMA because of ultrasound anomalies reported less frequent negative reactions, since they already anticipated abnormal results.

Introducing WES into prenatal 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; ability to access appropriate treatment and services; and particularly in the prenatal setting, local, state, and national abortion laws and decision-making about pregnancy termination. These issues and others will affect not only patients' decision-making regarding WES, but also their post-test needs for patient follow up, counseling and support. 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.

The investigator aims to examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes in undiagnosed prenatal cases.

Study Type

Interventional

Enrollment (Actual)

316

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • University of California San Francisco

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 62 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Women carrying a pregnancy with an ultrasound diagnosis of a major structural anomaly (or multiple anomalies) in a major organ system (cardiac, central nervous system, thorax, genito-urinary, gastrointestinal/ventral wall, skeletal and or multiple anomalies )
  • Clinical concern for a potential underlying genetic condition
  • Completed or plan to complete chorionic villus sampling or amniocentesis with chromosome analysis or microarray
  • Available maternal sample

Exclusion Criteria:

  • Prior WES performed for a clinical or research indication
  • Lack of phenotypic indication of a likely underlying genetic etiology
  • Mother unwilling or unable to provide a specimen

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Whole Exome Sequencing
Whole exome sequencing (WES) will take place for prenatal patients (pregnancies with fetal structural defects). All patients will get exome sequencing and will follow the same procedures.
Device: Whole Exome Sequencing (WES)
The Investigators will enroll pregnant women with fetal anomalies detected by ultrasound. Patients will be approached by a maternal-fetal specialist, who has counseled the patient regarding the fetal anomaly that has been detected. Written informed consent will be obtained by the study prenatal genetic counselor. Many patients will have undergone prenatal diagnostic testing in an outside laboratory; in such cases, cells or extracted DNA from the original fetal sample will be used for the purpose of this study. The consent process for prenatal WES will include pre-test counseling and the option of choosing whether or not to receive uncertain results and secondary findings. After conducting whole exome sequencing, the findings will be shared with the parent(s). Routine medical care will be provided to patients. The research will study the effectiveness of sequencing as a tool for providing genetic information to parents when a prenatal study reveals a fetus with a structural anomaly.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diagnostic Yield of Prenatal Exome in Patients With Fetal Structural Anomalies
Time Frame: Follow-up was done 6 months after return of exome results.
Number of prenatal patients (pregnancies with a structural anomaly) who got a positive exome result among those who had the exome test. Positive exome result is defined as identification of definitive or probable positive variants which explain prenatal phenotype.
Follow-up was done 6 months after return of exome results.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Investigators

  • Principal Investigator: Mary Norton, MD, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2017

Primary Completion (Actual)

May 13, 2022

Study Completion (Actual)

May 13, 2022

Study Registration Dates

First Submitted

March 16, 2018

First Submitted That Met QC Criteria

March 22, 2018

First Posted (Actual)

March 29, 2018

Study Record Updates

Last Update Posted (Actual)

April 14, 2023

Last Update Submitted That Met QC Criteria

March 22, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-22420

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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