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Diagnostic Utility of RNA-Seq in Neurodevelopmental Disorders

Presented by: Baylor College of Medicine, Undiagnosed Diseases Network (UDN)

 

Date of Release: December 21, 2020       

CME expiration date: December 21, 2023

Estimate time of completion: 1 hour

Course must be completed by the expiration date

www.acmgeducation.net

 

Session Description

Genome-wide testing technologies (including chromosomal microarrays, exome sequencing, and genome sequencing) have provided advances in diagnosis of genetic disorders.  This is particularly true for neurodevelopmental disorders, where sometimes nonspecific clinical presentations benefit from the more agnostic testing approach of a genome-wide technology.  However, these tests alone do not provide diagnoses for a majority of individuals undergoing the testing.  Utilizing three case examples from the Undiagnosed Diseases Network, we demonstrate how incorporation of RNA-seq analysis into the evaluation of individuals with neurodevelopmental disorders and previously nondiagnostic genomic evaluations has enabled the identification of their disease etiologies.  RNA-seq can aid in diagnosis through provision of evidence of functional impact of variants identified through other testing technologies or through identification of variants that were unable to be detected by standard testing technologies.  Furthermore, through the use of an RNA-seq-directed approach to genomic data analysis, diagnosis may become more efficient by allowing identification of variants with significant impacts on gene expression and/or splicing. 

 Target Audience

1. Clinical geneticists; genetic counselors; pediatric, obstetric, and maternal-fetal specialists; and all medical practitioners who are providing comprehensive diagnostic, management, and counseling services for patients with, or at risk for, genetically influenced health problems.
2. Laboratory directors and technicians who conduct genetic testing, researchers involved in the discovery of genetic disorders and treatments and any healthcare and public health professionals who have an in interest medical and clinical genetics and genomics.

Learning Objectives

 At the conclusion of the series, participants should be able to:

 

• Describe the clinical utility of whole exome/whole genome sequencing tests
• Identify clinical indications for whole exome/whole genome sequencing
• List determinants used to assess the probability of a variant’s pathogenicity

Session Learning Objectives

At the conclusion of this session, participants should be able to:

• Describe the clinical and diagnostic utility of RNA-seq in the evaluation of neurodevelopmental disorders
• Explain how an RNA-seq-directed approach to analysis of genomic data may be beneficial for the diagnosis of neurodevelopmental disorders
• Recognize the limitations of exome sequencing, genome sequencing, and chromosomal microarray testing
• Compare and contrast genomic variant identification and interpretation with and without RNA-seq

Presenters

David Murdock, MD, FACMG

Assistant Lab Director of CAP/CLIA-certified Human Genome Sequencing Center Clinical Lab
Baylor College of Medicine

 
Carlos Bacino, MD, FACMG

Medical Director Cytogenetics Laboratory, Baylor Genetics Laboratories

Vice Chair Clinical Affairs, Department of Molecular and Human Genetics Baylor College of Medicine

 

Hsiao-Tuan Chao, MD, PhD
Assistant Professor of Pediatrics-Neurology, Molecular and Human Genetics, and Neuroscience, 
Baylor College of Medicine

 

Jill Mokry, MS, CGC
Assistant Professor, Baylor College of Medicine

 

Financial Disclosures

Disclosure Statement

It is the policy of the American College of Medical Genetics and Genomics to plan and implement all of its educational activities in accordance with the ACCME Essentials and Areas and ACCME® Policies to ensure balance, independence, objectivity and scientific rigor. In accordance with the ACCME® Standards for Commercial Support, everyone (speakers, moderators, committee members and staff) who is in a position to control the content of an educational activity certified for AMA PRA Category 1 Credit™ is required to disclose all financial relationships with any commercial interests (see definition below) within the past 12 months that creates a real or apparent conflict of interest. Disclosure must include financial relationships of the individual and those of their spouse/partner. Individuals who do not disclose will be disqualified from participating in a CME activity.

This disclosure pertains to relationships with ACCME-defined commercial interests whose products or services may be related to the subject matter of the presentation topic. Any real or apparent conflicts of interest related to the content of the presentations must be managed prior to the educational activity. ACMG will identify, review and resolve all conflicts of interests prior to an educational activity being delivered to learners.

NOTE:

• ACMG will follow the ACCME’s expectation that no employees or owners of commercial interests will be involved as planners/faculty/presenters of a CME accredited activity.
• The ACCME definition of a commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.
• The ACCME does not consider providers of clinical service directly to patients to be commercial interests - unless the provider of clinical service is owned, or controlled by, an ACCME-defined commercial interest.
• Diagnostic laboratories are not considered commercial interests unless they are owned by or have a sister organization which is a commercial interest.

 

Staff - American College of Medical Genetics and Genomics
The following have nothing to disclose.
Jane Radford, MHA, CHCP
Claudia Barnett
Maximilian Muenke, MD, FACMG

David Murdock, MD, FACMG
Has no relevant financial relationships to disclose.

Carlos Bacino, MD, FACMG
Dr. Bacino has disclosed that he receives clinical research support from BioMarin and Ascendis, royalties from UpToDate, and consulting fees from Best Doctors.

Hsiao-Tuan Chao, MD, PhD
Has no relevant financial relationships to disclose.

Jill Mokry, MS, CGC
Ms. Mokry has disclosed that she receives a salary from Baylor Genetics Laboratories

 

Educational Credit

Accreditation Statement

The American College of Medical Genetics and Genomics is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Designation Statement

The American College of Medical Genetics and Genomics designates this enduring activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Claiming your Educational Credits

Pass a post-test with a score of 80% or better. Complete the activity evaluation form.

 

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Content Validation

ACMG follows the ACCME policy on Content Validation for CME activities, which requires:

 Content Validation and Fair Balance

1. ACMG follows the ACCME policy on Content Validation for CME activities, which requires:

1. All recommendations involving clinical medicine must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients.
2. All scientific research referred to, reported or used in CME in support or justification of patient care recommendations must conform to the generally accepted standards of experimental design, data collection and analysis.

 

2. Activities that fall outside the definition of CME/CE; “Educational activities that serve to maintain, develop, or increase the knowledge, skills, and professional performance and relationships that a physician uses to provide services for patients, the public, or the profession” (source: ACCME and AMA) will not be certified for credit. CME activities that promote recommendations, treatment, or manners of practicing medicine or pharmacy that are not within the definition of CME/CE or, are known to have risks or dangers that outweigh the benefits or, are known to be ineffective in the treatment of patients.
3. Presentations and CME/CE activity materials must give a balanced view of therapeutic options; use of generic names will contribute to this impartiality.  If the CME/CE educational materials or content includes trade names, where available, trade names from several companies must be used.

Off-label Uses of Products

When an off-label use of a product, or an investigational use not yet approved for any purpose, is discussed during an educational activity, the accredited sponsor shall require the speaker to disclose that the product is not labeled for the use under discussion, or that the product is still investigational. Discussions of such uses shall focus on those uses that have been subject of objective investigation.

Disclaimer

The ACMG does not endorse, or recommend the use of this educational program to make patient diagnoses, particular by individuals not trained in medical genetics. Adherence to the information provided in these programs does not necessarily ensure a successful diagnostic outcome. The program should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed at obtaining the same results. In determining the propriety of any specific procedure or test, a healthcare provider should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.