Aurélie Bourchany1, Christel Thauvin-Robinet2, Daphné Lehalle2, Ange-Line Bruel3, Alice Masurel-Paulet2, Nolwenn Jean2, Sophie Nambot2, Marjorie Willems4, Laetitia Lambert5, Salima El Chehadeh-Djebbar6, Elise Schaefer6, Aurélia Jaquette7, Judith St-Onge3, Charlotte Poe3, Thibaud Jouan3, Martin Chevarin3, Patrick Callier8, Anne-Laure Mosca-Boidron8, Nicole Laurent9, Mathilde Lefebvre3, Frédéric Huet1, Nada Houcinat2, Sébastien Moutton2, Christophe Philippe8, Frédéric Tran-Mau-Them8, Antonio Vitobello10, Paul Kuentz3, Yannis Duffourd3, Jean-Baptiste Rivière8, Julien Thevenon11, Laurence Faivre12. 1. Département de Pédiatrie 1, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, France; Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France. 2. Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, France. 3. Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France. 4. Département de Génétique Clinique, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France. 5. Unité Fonctionnelle de Génétique Clinique, Service de Médecine Néonatale, Maternité Régionale Universitaire, Nancy, France. 6. Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France. 7. Centre de Génétique, Hôpital de la Pitié-Salpétrière, Paris, France. 8. Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France; Laboratoire de Génétique chromosomique moléculaire, Plateau technique de Biologie, CHU, Dijon, France. 9. Laboratoire d'anatomopathologie, Plateau technique de Biologie, CHU, Dijon, France. 10. Laboratoire de Génétique chromosomique moléculaire, Plateau technique de Biologie, CHU, Dijon, France. 11. Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, France. Electronic address: jthevenon@chu-grenoble.fr. 12. Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, France. Electronic address: laurence.faivre@chu-dijon.fr.
Abstract
BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.
BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.
Authors: Kandamurugu Manickam; Monica R McClain; Laurie A Demmer; Sawona Biswas; Hutton M Kearney; Jennifer Malinowski; Lauren J Massingham; Danny Miller; Timothy W Yu; Fuki M Hisama Journal: Genet Med Date: 2021-07-01 Impact factor: 8.822
Authors: Karl W Doerfer; Tara Sander; Girija G Konduri; David R Friedland; Joseph E Kerschner; Christina L Runge Journal: Laryngoscope Investig Otolaryngol Date: 2020-05-20
Authors: Jennifer Malinowski; David T Miller; Scott E Hickey; Jun Shen; Laurie Demmer; Jennifer Gannon; Elaine Maria Pereira; Molly C Schroeder; Maren T Scheuner; Anne Chun-Hui Tsai Journal: Genet Med Date: 2020-03-23 Impact factor: 8.822
Authors: Claudia C Y Chung; Gordon K C Leung; Christopher C Y Mak; Jasmine L F Fung; Mianne Lee; Steven L C Pei; Mullin H C Yu; Vivian C C Hui; Joshua C K Chan; Jeffrey F T Chau; Marcus C Y Chan; Mandy H Y Tsang; Wilfred H S Wong; Joanna Y L Tung; Kin Shing Lun; Yiu Ki Ng; Cheuk Wing Fung; Mabel S C Wong; Rosanna M S Wong; Yu Lung Lau; Godfrey C F Chan; So Lun Lee; Kit San Yeung; Brian H Y Chung Journal: Lancet Reg Health West Pac Date: 2020-07-24