Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses

Aurélie Bourchany (1, 2) , Christel Thauvin-Robinet (1, 3) , Daphne Lehalle (1, 3) , Ange-Line Bruel (1) , Paul Masurel-Paulet (1, 3, 4) , Nolwenn Jean (1, 3, 4) , Sophie Nambot (3, 4, 1) , Marjorie Willems (5) , Laetitia Lambert (6) , Salima El Chehadeh-Djebbar (7) , Elise Schaefer (7) , Aurélia Jaquette (8) , Judith St-Onge (1) , Charlotte Poe (1) , Thibaud Jouan (1) , Martin Chevarin (1) , Patrick Callier (1, 9) , Anne-Laure Mosca-Boidron (9, 1) , Nicole Laurent (10) , Mathilde Lefebvre (1) , Frédéric Huet (2, 1) , Nada Houcinat (3, 1) , Sébastien Moutton (3, 1) , Christophe Philippe (1, 9) , Frédéric Tran-Mau-Them (1, 9) , Antonio Vitobello (9) , Paul Kuentz (1) , Yannis Duffourd (1) , Jean-Baptiste Rivière (1, 9) , Julien Thevenon (1, 3) , Laurence Faivre (3, 1)

1 Equipe GAD (LNC - U1231)
2 Service de pédiatrie (CHU de Dijon)
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 FHU TRANSLAD (CHU de Dijon)
5 Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier]
6 Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy]
7 Nouvel Hôpital Civil de Strasbourg
8 CHU Pitié-Salpêtrière [AP-HP]
9 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
10 Service de Pathologie [CHU de Dijon]

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. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Mots clés: Diagnostic turnaround time; Exome sequencing; Undiagnosed genetic conditions

Domaines: Génétique

Aurélie Bourchany, Christel Thauvin-Robinet, Daphne Lehalle, Ange-Line Bruel, Paul Masurel-Paulet, et al.. Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses. European Journal of Medical Genetics, 2017, 60 (11), pp.595 - 604. ⟨10.1016/j.ejmg.2017.08.011⟩. ⟨hal-01626052⟩