Positive Impact of Expert Reference Center Validation on Performance of Next-Generation Sequencing for Genetic Diagnosis of Autoinflammatory Diseases.

Boursier G1, Rittore C2, Georgin-Lavialle S3, Belot A4, Galeotti C5, Hachulla E6, Hentgen V7, Rossi-Semerano L8, Sarrabay G9, Touitou AI10.

Author information

1: Department of Medical Genetics, Rare Diseases and Personalized Medicine, CHU Montpellier, Rare and Autoinflammatory diseases unit, Univ Montpellier, 34295 Montpellier, France. g-boursier@chu-montpellier.fr.
2: Department of Medical Genetics, Rare Diseases and Personalized Medicine, CHU Montpellier, Rare and Autoinflammatory diseases unit, Univ Montpellier, 34295 Montpellier, France. cecile.rittore@inserm.fr.
3: Department of Internal Medicine, CEREMAIA, Tenon Hospital, AP-HP, University of Pierre et Marie Curie, 75970 Paris, France. sophie.georgin-lavialle@aphp.fr.
4: Paediatric Nephrology, Rheumatology, Dermatology Unit, RAISE, HFME, HCL, Univ Lyon, 69677 Bron, France. alexandre.belot@chu-lyon.fr.
5: Department of Paediatric Rheumatology, CEREMAIA, Bicêtre Hospital, AP-HP, 94275 Le Kremlin-Bicêtre, France. caroline.galeotti@aphp.fr.
6: Department of Internal Medicine and Clinical Immunology, CHU Lille, University of Lille, 59037 Lille, France. Eric.HACHULLA@chru-lille.fr.
7: Department of General Pediatrics, CEREMAIA, CH Versailles, 78157 Le Chesnay, France. vhentgen@ch-versailles.fr.
8: Department of Paediatric Rheumatology, CEREMAIA, Bicêtre Hospital, AP-HP, 94275 Le Kremlin-Bicêtre, France. linda.rossi@aphp.fr.
9: Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, INSERM, University Montpellier, Department of Medical Genetics, Rare Diseases and Personalized Medicine, CEREMAIA, CHU Montpellier, 34295 Montpellier, France. guillaume.sarrabay@inserm.fr.
10: Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, INSERM, University Montpellier, Department of Medical Genetics, Rare Diseases and Personalized Medicine, CEREMAIA, CHU Montpellier, 34295 Montpellier, France. isabelle.touitou@inserm.fr.

Abstract

Monogenic autoinflammatory diseases (AIDs) are caused by variants in genes that regulate innate immunity. The current diagnostic performance of targeted next-generation sequencing (NGS) for AIDs is low. We assessed whether pre-analytic advice from expert clinicians could help improve NGS performance from our 4 years of experience with the sequencing of a panel of 55 AIDs genes. The study included all patients who underwent routine NGS testing between September 2014 and January 2019 at the laboratory of autoinflammatory diseases (Montpellier, France). Before March 2018, all medical requests for testing were accepted. After this time, we required validation by a reference center before NGS: the positive advice could be obtained after a face-to-face consultation with the patient or presentation of the patient's case at a multidisciplinary staff meeting. Targeted NGS resulted in an overall 7% genetic confirmation, which is consistent with recent reports. The diagnostic performance before and after implementation of the new pre-requisite increased from 6% to 10% (p = 0.021). Our study demonstrated, for the first time, the beneficial effect of a two-step strategy (clinical expert advice, then genetic testing) for AIDs diagnosis and stressed the possible usefulness of the strategy in anticipation of the development of pan-genomic analyses in routine settings.