Prenatal WES: Clinical Utility of Prenatal Whole Exome Sequencing
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
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N/A |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: WES Whole exome sequencing (WES) will take place. |
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.
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Outcome Measures
Primary Outcome Measures
- Clinical Utility (CU) of WES- a composite measure [At the completion of data collection (follow-up visit at 6-12 months after return of results for WES)]
CU covers: a) Pregnancy termination; b) In-utero medical or surgical intervention; c) Perinatal decision making- including antepartum surveillance for fetal distress; location and mode of delivery; decisions for non-intervention or perinatal hospice care; d) Immediate neonatal management; e) Reproductive decision making and counseling subsequent to the index pregnancy.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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 )
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Clinical concern for a potential underlying genetic condition
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Completed or plan to complete chorionic villus sampling or amniocentesis with chromosome analysis or microarray
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Available maternal sample
Exclusion Criteria:
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Prior WES performed for a clinical or research indication
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Lack of phenotypic indication of a likely underlying genetic etiology
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Mother unwilling or unable to provide a specimen
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California San Francisco | San Francisco | California | United States | 94143 |
Sponsors and Collaborators
- University of California, San Francisco
Investigators
- Principal Investigator: Mary Norton, MD, University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
- Chervenak FA, McCullough LB. Ethical issues in perinatal genetics. Semin Fetal Neonatal Med. 2011 Apr;16(2):70-3. doi: 10.1016/j.siny.2010.10.004. Epub 2010 Nov 3. Review.
- Cowan RS. Aspects of the history of prenatal diagnosis. Fetal Diagn Ther. 1993 Apr;8(Suppl. 1):10-7.
- Donley G, Hull SC, Berkman BE. Prenatal whole genome sequencing: just because we can, should we? Hastings Cent Rep. 2012 Jul-Aug;42(4):28-40. doi: 10.1002/hast.50. Epub 2012 Jun 20.
- Norton ME, Rink BD. Changing indications for invasive testing in an era of improved screening. Semin Perinatol. 2016 Feb;40(1):56-66. doi: 10.1053/j.semperi.2015.11.008. Epub 2015 Dec 24. Review.
- 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.
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