Presented by members of the Washington University in St. Louis UDN Clinical Site

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.

Overall 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:

 Recognize the clinical features of CHARGE syndrome.

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

 Intended 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.

Faculty

Jorge Luis Granadillo De Luque, MD
Instructor in Pediatrics, Genetics and Genomic Medicine, Washington University in St. Louis

Daniel Wegner, MS

Lab Manager, Department of Pediatrics, Washington University in St. Louis

Tomi Toler, MS, CGC

Clinical Genetic Counselor, Washington University in St. Louis