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The Genome
CMECNE

The Exome and Whole Exome Sequencing: Prenatal Testing Recommendations

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Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Contrast ‘the exome’ with ‘whole exome sequencing’
2. Recall what constitutes a VUS

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Dec 31 2021, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Read Disclaimer & Fine Print

WHAT IS IT?

  • The exome refers to the expressed regions of the genome, or the exons, which code for proteins
    • The exome constitutes about 2%-3% of the genome
    • There are about 180,000 exons in the over 20,000 genes in the human genome

DNA sequence analysis of all of the expressed genes in the genome is referred to as Whole Exome Sequencing (WES) or now more commonly referred to as Exome Sequencing (ES) in the professional literature

  • WES  generally allows for simultaneous analysis of all exons in one test
    • WES  will analyze close to 95% of the exons
  • WES is usually considered for individuals with rare diseases or syndrome for whom testing of specific potentially disease causing genes have not identified any disease causing gene mutations
  • WES will not detect all types of genetic changes in the exome, so there are limitations
  • Costs tend to be lower than whole genome sequencing (WGS)

WES Indications for Prenatal Diagnosis

  • ISPD  / SMFM / PQF joint recommendation (see ‘Related ObG Topics’ below) states “Exome sequencing is an emerging technology for the evaluation of the fetus with structural anomalies that are detected on ultrasound”

ISPD/ SMFM / PQF

Routine use of Prenatal Sequencing

  • The routine use of prenatal sequencing is not recommended, including cases where fetal DNA has already been obtained via amniocentesis, CVS or cordocentesis
    • Clinical validation data are currently insufficient and prospective studies are required to determine clinical utility and risks vs harms

Appropriate Circumstances to Consider Prenatal Sequencing in a Non-Research Setting

  • Fetal anomalies or a single major anomaly suggestive of a genetic disorder
    • Microarray is negative
    • No microarray results is available but the fetus exhibits anomalies strongly suggesting of a single gene disorder
  • Previous undiagnosed fetus (or child) from either parent, with single or multiple anomalies suspicious for a genetic syndrome that has now recurred in the current pregnancy
    • Karyotype and microarray in the current pregnancy have not yielded a diagnosis
    • Make every effort to obtain a sample from the current pregnancy or previously affected offspring
    • If samples are unavailable from previously affected offspring or the current pregnancy, consider offering parents sequencing to determine if they may be carriers for an autosomal recessive disorder
  • History of recurrent stillbirths with negative karyotype and/or microarray, where the fetus is exhibiting a similar pattern of anomalies

ACMG

Consider WES for the Following

  • Fetus with ultrasound anomalies and no results from CMA and karyotype
    • In the case of concern related to a specific phenotype or disorder, start with more targeted molecular testing  (single-gene test or gene panel)
  • Do not use WES for other indications such as soft markers for Down syndrome or recurrent pregnancy loss

KEY POINTS:

  • WES analysis will generally require a blood sample
    • Requirements will vary by laboratory
  • Results from WES will not always yield definitive, actionable results that confirm a diagnosis
    • Findings may indicate a Variant of Uncertain Significance (VUS) that may be tracked over time to determine if the variant is ultimately benign or pathogenic
    • WES testing may often be most informative when an individual’s family members are also tested or willing to be tested to clarify result interpretation
  • Genetic counseling is recommended pre and post WES analysis
  • Thorough informed consent process is imperative given the potential for results that may or may not be definitive

Additional Points When Considering use in Prenatal Period (ACMG)

  • WES result yield is higher with
    • Accurate, comprehensive clinical information | Successful interpretation of variants dependent on accuracy of phenotype
    • Trios: Samples from mother, father and fetus that can be used for molecular analysis
  • Labs should report back
    • Variants that are likely and known pathogenic
    • Consider reporting VUS “in genes that fit the fetal phenotype, especially in autosomal recessive conditions if the VUS is found in trans with a pathogenic or likely pathogenic variant”

Incidental Findings (genetic findings not related to the fetal phenotype and not on ACMG secondary findings list)

  • Report highly penetrant pathogenic variants that are known to cause moderate to severe childhood onset disorders
  • Do not report if there is no known fetal or childhood phenotype, even if the variant involves a severe disorder
  • Do not report fetal carrier status for
    • Autosomal recessive (male and female fetuses)
    • X-linked disorders (female fetuses)

Secondary Findings (on ACMG list of known pathogenic variants that should be reported as lifesaving interventions may be available) 

  • It is important that the issue of secondary findings be addressed in the consent, including if positive results should be reported for fetus only, or parents too
  • ‘Opt out’ option should be available

Misattributed Parentage

  • Not specific to WES, but especially with trio samples, it may come to light that a parent is not the biologic parent (e.g, mistaken paternity)
    • Critical that this possibility be included in pretest counseling and laboratories should have policies in place to deal with this issue

Reanalysis

  • It may be reasonable to reanalyze results after 12 months (or sooner at the discreation of the lab) if there is no definitive answer  because
    • Children may manifest new signs and symptoms that further refine the phenotype
    • New genetic discoveries are being uploaded daily to databases and may contribute to a final molecular dignosis

Learn More – Primary Sources:

The Promise of Whole-Exome Sequencing in Medical Genetics

ACMG: Points to Consider for Informed Consent for Genome/Exome Sequencing

10 Things Exome Sequencing Can’t Do-but Why It’s Still Powerful

ACOG Committee Opinion 682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

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Related ObG Topics:

ISPD, SMFM and PQF Release a Joint Position Statement on Fetal Genome-Wide Sequencing
The Chromosome – Structure and Number
The Genome and Whole Genome Sequencing
Can Whole-Exome Sequencing Help Diagnose Otherwise Unexplained Fetal Structural Anomalies?

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OBG Project CME requires a modern web browser (Internet Explorer 10+, Mozilla Firefox, Apple Safari, Google Chrome, Microsoft Edge). Certain educational activities may require additional software to view multimedia, presentation, or printable versions of their content. These activities will be marked as such and will provide links to the required software. That software may be: Adobe Flash, Apple QuickTime, Adobe Acrobat, Microsoft PowerPoint, Windows Media Player, or Real Networks Real One Player.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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