HGG Advances (Jul 2022)
Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study
- Alison M. Elliott,
- Shelin Adam,
- Christèle du Souich,
- Anna Lehman,
- Tanya N. Nelson,
- Clara van Karnebeek,
- Emily Alderman,
- Linlea Armstrong,
- Gudrun Aubertin,
- Katherine Blood,
- Cyrus Boelman,
- Cornelius Boerkoel,
- Karla Bretherick,
- Lindsay Brown,
- Chieko Chijiwa,
- Lorne Clarke,
- Madeline Couse,
- Susan Creighton,
- Abby Watts-Dickens,
- William T. Gibson,
- Harinder Gill,
- Maja Tarailo-Graovac,
- Sara Hamilton,
- Harindar Heran,
- Gabriella Horvath,
- Lijia Huang,
- Gurdip K. Hulait,
- David Koehn,
- Hyun Kyung Lee,
- Suzanne Lewis,
- Elena Lopez,
- Kristal Louie,
- Karen Niederhoffer,
- Allison Matthews,
- Kirsten Meagher,
- Junran J. Peng,
- Millan S. Patel,
- Simone Race,
- Phillip Richmond,
- Rosemarie Rupps,
- Ramona Salvarinova,
- Kimberly Seath,
- Kathryn Selby,
- Michelle Steinraths,
- Sylvia Stockler,
- Kaoru Tang,
- Christine Tyson,
- Margot van Allen,
- Wyeth Wasserman,
- Jill Mwenifumbo,
- Jan M. Friedman
Affiliations
- Alison M. Elliott
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Women’s Health Research Institute, Vancouver, BC, Canada; Corresponding author
- Shelin Adam
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Christèle du Souich
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Anna Lehman
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Tanya N. Nelson
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Clara van Karnebeek
- Department of Pediatrics, Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada; Department of Pediatrics, Emma Children’s Hospital, Amsterdam, University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Emily Alderman
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Linlea Armstrong
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Gudrun Aubertin
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Katherine Blood
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Cyrus Boelman
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Cornelius Boerkoel
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Karla Bretherick
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Lindsay Brown
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Chieko Chijiwa
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Lorne Clarke
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Madeline Couse
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Susan Creighton
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Abby Watts-Dickens
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- William T. Gibson
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Harinder Gill
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Maja Tarailo-Graovac
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Sara Hamilton
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Harindar Heran
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Gabriella Horvath
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Lijia Huang
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Gurdip K. Hulait
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- David Koehn
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Hyun Kyung Lee
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Suzanne Lewis
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Elena Lopez
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Kristal Louie
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Karen Niederhoffer
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Allison Matthews
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Kirsten Meagher
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Junran J. Peng
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Millan S. Patel
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Simone Race
- Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Phillip Richmond
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Rosemarie Rupps
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Ramona Salvarinova
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Kimberly Seath
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Kathryn Selby
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Michelle Steinraths
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Sylvia Stockler
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
- Kaoru Tang
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Christine Tyson
- Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
- Margot van Allen
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Wyeth Wasserman
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada; Department of Pediatrics, Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
- Jill Mwenifumbo
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Jan M. Friedman
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Journal volume & issue
-
Vol. 3,
no. 3
p. 100108
Abstract
Summary: Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual’s full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results.Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.
