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. 

Harrison Brand, PhD

Assistant Professor

MGH and Harvard Medical School

Dr. Harrison Brand is an Assistant Professor in the Departments of Neurology and Surgery at Massachusetts General Hospital (MGH) and Harvard Medical School. He also serves as the Associate Director of the Broad Structural Variation Group. Research in his lab focuses on the development of novel methods for the analysis of structural variation (SV) from whole genome sequencing data and application of these methods to decipher the genetic architecture of structural birth defects and other developmental disorders. He served as one of the primary developers of the cloud-based GATK structural variant caller (GATK-SV) and has led efforts to generate robust SV reference databases for the genomic community in cohorts such as gnomAD, 1000 genomes, and All of Us. 

Anne O'Donnell-Luria, MD, PhD

Assistant Professor, Boston Children's Hospital and Institute Member

Broad Institute of MIT and Harvard

Sara Cullinan, PhD (Moderator)

Deputy Editor

American Journal of Human Genetics


August Journal Club
08/14/2024 at 12:00 PM (EDT)  |  30 minutes
08/14/2024 at 12:00 PM (EDT)  |  30 minutes August Journal Club - AJHG