Clinical Utility of Prenatal Whole Exome Sequencing
Condition: Structural Anomalies; Cardiac Anomalies; Central Nervous System Anomalies; Thorax Anomalies; Genito-urinary Anomalies; Gastrointestinal Anomalies; Skeletal Anomalies; Multiple Anomalies
MeSH terms: Nervous System Malformations; Urogenital Abnormalities; Heart Defects, Congenital; Congenital Abnormalities; Abnormalities, Multiple
Study type: Interventional

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.
    

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.
    

Intervention name(s): Whole Exome Sequencing (WES)
Intervention type(s): Device
Intervention description(s): 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.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic