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.
Highlights
Monogenic autoinflammatory diseases (AIDs) are characterized by variants in genes coding proteins involved in innate immunity [1]
The main steps leading to genetic testing require the exclusion of infectious, autoimmune, or malignant diseases and the search for specific demographics and clinical characteristics, including the evolution of inflammatory episodes
The following situations were not considered consistent with the diagnosis: one heterozygote class 4 or 5 variant or two rare variants of uncertain significance (VOUS) identified in a recessive condition; variants not segregated with the phenotype; and frequent VOUS, such as MEFV:p.(Glu148Gln) or TNFRSF1A:p.(Arg121Gln)
Summary
Monogenic autoinflammatory diseases (AIDs) are characterized by variants in genes coding proteins involved in innate immunity [1]. Next-generation sequencing (NGS) allows for investigating multiple genes simultaneously at a manageable cost and has become the preferred method for molecular testing of AIDs [6]. This strategy is of particular interest for detecting low-level mosaic variants and copy-number variations (CNV) [7]. Our reference center (CeRéMAIA) is specialized in AIDs. Here, we presented the results of our 4 years of experience with targeted analysis of a panel of 55 known AIDs genes as a routine NGS-based strategy and compared its performance (i.e., the frequency of conclusive genetic diagnosis) before and after implementation of new pre-requisite, involving approval for this testing from a national reference center for AIDs
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