TY - JOUR
T1 - Genome-wide sequencing and the clinical diagnosis of genetic disease
T2 - The CAUSES study
AU - Elliott, Alison M.
AU - Adam, Shelin
AU - du Souich, Christèle
AU - Lehman, Anna
AU - Nelson, Tanya N.
AU - van Karnebeek, Clara
AU - Alderman, Emily
AU - Armstrong, Linlea
AU - Aubertin, Gudrun
AU - Blood, Katherine
AU - Boelman, Cyrus
AU - Boerkoel, Cornelius
AU - Bretherick, Karla
AU - Brown, Lindsay
AU - Chijiwa, Chieko
AU - Clarke, Lorne
AU - Couse, Madeline
AU - Creighton, Susan
AU - Watts-Dickens, Abby
AU - Gibson, William T.
AU - Gill, Harinder
AU - Tarailo-Graovac, Maja
AU - Hamilton, Sara
AU - Heran, Harindar
AU - Horvath, Gabriella
AU - Huang, Lijia
AU - Hulait, Gurdip K.
AU - Koehn, David
AU - Lee, Hyun Kyung
AU - Lewis, Suzanne
AU - Lopez, Elena
AU - Louie, Kristal
AU - Niederhoffer, Karen
AU - Matthews, Allison
AU - Meagher, Kirsten
AU - Peng, Junran J.
AU - Patel, Millan S.
AU - Race, Simone
AU - Richmond, Phillip
AU - Rupps, Rosemarie
AU - Salvarinova, Ramona
AU - Seath, Kimberly
AU - Selby, Kathryn
AU - Steinraths, Michelle
AU - Stockler, Sylvia
AU - Tang, Kaoru
AU - Tyson, Christine
AU - van Allen, Margot
AU - Wasserman, Wyeth
AU - Mwenifumbo, Jill
AU - Friedman, Jan M.
N1 - Funding Information: We are truly grateful to the families who participated in the CAUSES study and all the referring physicians and genetic counselors. We would also like to thank the secretarial staff of the Provincial Medical Genetics Program (in particular Margaret Sankowski and Ashley Wallace), Sheryl Atkinson, the BCCHR IT Support Team, Rhea Beauchesne, Lynne Beszant, Patricia Birch, Jocelyn Carter-Sim, Rachel Coe, Courtney B. Cook, Alivia Dey, Adrienne Elbert, Jane Gillis, Liza Mak, Anne MacDougall, Patricia Power, Dawn Siciliano, Angela Siemens, Emma Strong, Tracy Tucker, Tasha Wainstein, and the Provincial Medical Genetics Program, Department of Pediatrics, Department of Pathology and Laboratory Medicine, BC Women's Hospital and BC Children's Hospital. Investigators in the CAUSES study (Clinical Assessment of the Utility of Sequencing as a Service) include Shelin Adam, Christèle du Souich, Alison M. Elliott, A.L. J.M. T.N.N. C.K. and J.M.F. (PI). The bioinformatic pipeline used in part of the CAUSES study was developed in the laboratory of W.W. The CAUSES project was funded by the Mining for Miracles (BCCH Foundation) and Genome British Columbia, with support from the British Columbia Provincial Health Services Authority and British Columbia Women's Hospital. A.M.E. S.A. C.D.S. A.L. T.N. C.V.K. and J.M.F. contributed to the conception and study design. All authors contributed to data acquisition. A.M.E. and J.M.F. drafted the manuscript and all authors contributed to critical review and editing of the manuscript. A.M.E. S.A. C.D.S. A.L. T.N. and J.M.F. accessed and verified the data. The authors declare no competing interests. Funding Information: Investigators in the CAUSES study (Clinical Assessment of the Utility of Sequencing as a Service) include Shelin Adam, Christèle du Souich, Alison M. Elliott, A.L., J.M., T.N.N., C.K., and J.M.F. (PI). The bioinformatic pipeline used in part of the CAUSES study was developed in the laboratory of W.W. The CAUSES project was funded by the Mining for Miracles ( BCCH Foundation) and Genome British Columbia , with support from the British Columbia Provincial Health Services Authority and British Columbia Women's Hospital . Publisher Copyright: © 2022 The Authors
PY - 2022/7/14
Y1 - 2022/7/14
N2 - 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.
AB - 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.
KW - diagnostic rate
KW - exome sequencing
KW - genetic counseling
KW - genome sequencing
KW - multidisciplinary approach
KW - reanalysis
KW - reinterpretation
UR - http://www.scopus.com/inward/record.url?scp=85130394833&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.xhgg.2022.100108
DO - https://doi.org/10.1016/j.xhgg.2022.100108
M3 - Article
C2 - 35599849
SN - 2666-2477
VL - 3
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100108
ER -