Full clinical picture & revisiting test results important
This massive study of 500 families by a multidisciplinary team established a diagnosis of genetic disease in 43% of families on initial interpretation and a further 17% on follow-up and reinterpretation over time.
Success was attributed to:
- using trio sequencing (both parents and child)
- having a multidisciplinary team consider the full clinical picture
- and with regular follow-up and reinterpretation of genetic test results as needed.
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 counsellors, pediatric subspecialists, 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, bio-informaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.
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SOURCE: HGG Adv. 2022 Jul 14; 3(3): 100108. Published online 2022 Apr 18. doi: 10.1016/j.xhgg.2022.100108 © 2022 The Authors.
Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study
Alison M. Elliott, 1,2,3,* Shelin Adam,1,2 Christe‘le du Souich, 1,2 Anna Lehman,1,2 Tanya N. Nelson, 4 Clara van Karnebeek, 5,6 Emily Alderman, 1 Linlea Armstrong, 1,2 Gudrun Aubertin, 1 Katherine Blood, 1 Cyrus Boelman, 2,7 Cornelius Boerkoel, 1,2 Karla Bretherick, 4 Lindsay Brown, 4 Chieko Chijiwa, 1 Lorne Clarke, 1,2 Madeline Couse, 1 Susan Creighton,1 Abby Watts-Dickens, 1 William T. Gibson, 1,2 Harinder Gill, 1 Maja Tarailo-Graovac, 2 Sara Hamilton, 1 Harindar Heran, 1 Gabriella Horvath, 2,8 Lijia Huang, 4 Gurdip K. Hulait, 1 David Koehn, 1 Hyun Kyung Lee, 1 Suzanne Lewis, 1,2 Elena Lopez,1,2 Kristal Louie, 1 Karen Niederhoffer,1 Allison Matthews, 4 Kirsten Meagher, 1 Junran J. Peng,2 Millan S. Patel,1,2 Simone Race,8 Phillip Richmond,2 Rosemarie Rupps, 1 Ramona Salvarinova, 2,8 Kimberly Seath, 1 Kathryn Selby, 2,7 Michelle Steinraths, 1 Sylvia Stockler,2,8 Kaoru Tang,1 Christine Tyson, 4 Margot van Allen, 1,2 Wyeth Wasserman,1,2,5 Jill Mwenifumbo, 2 and Jan M. Friedman 1,2
1. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
2. BC Children’s Hospital Research Institute, Vancouver, BC, Canada
3. Women’s Health Research Institute, Vancouver, BC, Canada
4. Division of Genome Diagnostics, Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospitals, Vancouver, BC, Canada
5. Department of Pediatrics, Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada
6. Department of Pediatrics, Emma Children’s Hospital, Amsterdam, University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
7. Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
8. Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada