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:
- 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
- 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.
- Identify some of the limitations of current clinical genetic testing in patients with CHARGE syndrome.
- 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
This course does not offer educational credits