Session Description

CHD7 pathogenic variants cause more than 90% of CHARGE syndrome cases. Approximately 10% have no known genetic cause. We report the case of a patient with clinical features of CHARGE syndrome who lacked molecular confirmation despite a lengthy and comprehensive genetic evaluation.

After enrollment in the Undiagnosed Diseases Network, genome-wide methylation analysis revealed an abnormal methylation pattern consistent with the CHD7-associated epigenetic signature.  Genome sequencing with focused bioinformatic analysis of CHD7 and removal of all variant filters detected a de novo 15 bp deletion in intron 4 of CHD7. RNA studies confirmed that this deletion causes disruption of the canonical 3’ splice site, and introduction of a premature stop codon. 

In conclusion, integrating genomic, epigenomic, and transcriptomic methods may increase the diagnostic yield for CHARGE and other genetic syndromes.

 Learning Objectives

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

1. Describe the clinical utility of whole exome/whole genome sequencing tests
2. Identify clinical indications for whole exome/whole genome sequencing
3. List determinants used to assess the probability of a variant’s pathogenicity
4. Elaborate on the importance of pre-test counseling and consent

Session Learning Objectives

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

1. Recognize the clinical features of CHARGE syndrome. 
2. Identify some of the limitations of current clinical genetic testing in patients with CHARGE syndrome.
3. Integrate various and newer genetic techniques (methylation, transcription, and genomic analysis) in the evaluation of a patient with CHARGE syndrome.

 
Faculty:

Jorge Luis Granadillo De Luque, MD

Instructor in Pediatrics, Genetics and Genomic Medicine, Washington University in St. Louis

Daniel Wegner, MS

Department of Pediatrics, Washington University in St. Louis

Tomi Toler, MS, CGC

Genetic Counselor, Washington University in St. Louis

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 CME Credits

Complete the activity and carefully take the CME quiz. You can take the quiz as many times as you like until you complete it successfully. Physicians who complete the CME course and score at least 80 percent correct on the quiz are eligible for credits.  Next, complete evaluation form.  You can view and print a certificate awarding 1 AMA PRA Category 1 Credits™.

CME Course Expiration

Enduring materials: Three years after the specific activity date.  See expiration date.

 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.

Off-label Drug Use statement

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.

Disclosures of Financial Relationships

Planning Committee:

Anne Slavotinek, MB.BS., PhD, FACMG

ACMG Education Committee Chair and Liaison to the Program Committee

Disclosures: Grant/Research Support National Eye Institute and National Institutes of Health; Royalties: Oxford University Press, UptoDate

John Bernat, MD, PhD, FACMG

University of Iowa

Disclosures: Grant/research support: Idorsia, Pfizer, Protalix, Sanofi Genzyme, Takeda. Advisory boards: Sanofi Genzyme, Takeda

Staff - American College of Medical Genetics and Genomics

The following have nothing to disclose.

Jane Radford, MHA, CHCP

Claudia Barnett

Michael Watson, PhD, FACMG

Presenter Disclosures:

Jorge Luis Granadillo De Luque, MD

Instructor in Pediatrics, Genetics and Genomic Medicine, Washington University in St. Louis

Has no relevant financial relationships to disclose.

Daniel Wegner, MS

Department of Pediatrics, Washington University in St. Louis

Has no relevant financial relationships to disclose.

Tomi Toler, MS, CGC

Genetic Counselor, Washington University in St. Louis

Has no relevant financial relationships to disclose.

Full Course Description