Exome CNV detection and classification in rare diseases

Includes a Live Web Event on 08/14/2024 at 12:00 PM (EDT)

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Dr. Gabrielle Lemire will discuss exome copy number variant (CNV) detection, analysis and classification on a cohort of 6,633 families with undiagnosed rare genetic disorders. With the resolution provided by exome sequencing, they identified a causative CNV in 2.6% of families and assessed CNV pathogenicity by applying an advanced classification approach.

Overview of Presentation

CNVs can be difficult to identify by standard exome sequencing and challenges still remain in accurate classification of CNV pathogenicity.
CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics.
The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%).
To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework.
We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance.
Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing.

Gabrielle Lemire, MD, FRCPC

Research Fellow

Boston Children’s Hospital; Broad Institute of MIT and Harvard

Dr. Gabrielle Lemire is a medical geneticist certified under the Royal College of Physicians of Canada who currently trains at Boston Children’s Hospital and Broad Institute of MIT and Harvard. She completed her medical and residency training in medical genetics at Université de Montréal and a clinical research fellowship with the Care4Rare Canada Consortium at the University of Ottawa. She is currently a postdoctoral research fellow in Dr. Anne O’Donnell-Luria’s laboratory at Boston Children’s Hospital. Dr Lemire performs exome and genome analyses to identify rare disease diagnoses and novel gene discovery. Her research focuses on developing novel approaches to investigate undiagnosed rare genetic diseases, understanding their molecular mechanism, and improve phenotype delineation of rare diseases.